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February 2026
January 2026 December 2025 November 2025 October 2025 September 2025 August2025 July 2025 June2025 June2025 May 2025 April 2025 March 2025 February 2025 January 2025 December 2024 November 2024 October 2024 September 2024 August 2024 July 2024 June 2024 May 2024 April 2024 March 2024 February 2024 January 2024 December 2022 December 2021 December 2020 December 2019 | Sears, J. C., Broadie, K. (2025). PKA restricts ERK signaling in learning and memory Kenyon cell neurons. Cell Signal, 132:111818 PubMed ID: 40250698
Summary: Protein Kinase A (PKA) and Extracellular Signal-Regulated Kinase (ERK) have core roles in learning and memory. This study investigated kinase-kinase signaling interactions in the Drosophila brain Kenyon cell learning/memory circuit using separation of phases-based activity reporter of kinase (SPARK) biosensors to image circuit-localized functions in vivo. We find that constitutively active Rapidly Accelerated Fibrosarcoma (RAF(gof)) enhances ERK signaling only in Kenyon cell domains with low baseline PKA signaling, and that transgenic inhibition of PKA function elevates ERK signaling. Conversely, loss of ERK has no impact on PKA signaling, whereas RAF(gof) expands PKA signaling. Importantly, transgenic PKA inhibition together with RAF(gof) synergistically elevates ERK signaling. These findings indicate a negative PKA-ERK pathway interaction within learning/memory Kenyon cells. Potentiating circuit activity using an exogenous NaChBac ion channel elevates PKA signaling in circuit domains with low baseline PKA function, and uniformly strongly increases ERK signaling. Similarly, thermogenetic stimulation of circuit activity with a temperature-sensitive TRPA1 channel increases PKA signaling in circuit domains of low baseline PKA, and elevates ERK signaling. Importantly, potentiating circuit activity (NaChBac) while also inhibiting PKA function synergistically elevates ERK signaling. Likewise, conditional induction of circuit activity (TRPA1) together with PKA inhibition increases activity-dependent ERK signaling. Finally, a mechanically-induced seizure model (bang-sensitive sesB mutant) elevates PKA signaling, while simultaneous transgenic PKA inhibition in this model acts to synergistically increase ERK signaling. Taken together, it is concluded that PKA limits ERK signaling in Kenyon cells within the learning and memory circuit, with PKA function acting to restrict activity-dependent ERK signaling. | Matos, Y. B., Velichkova, N., Kirchknopf Riera, M., da Luz, M. G. E., Berni, J. (2025).. Characterizing stage-dependent neuromotor patterns in Drosophila melanogaster larvae through a graph construction approach. Front Neurosci, 19:1557624 PubMed ID: 40182146
Summary: This study investigated developmental changes in neuromotor activity patterns in Drosophila melanogaster larvae by combining calcium imaging with a novel graph-based mathematical framework. This allows to perform relevant quantitative comparisons between first (L1) and early third (L3) instar larvae. L1 larvae were found to exhibit higher frequencies of spontaneous neural activity that fail to propagate, indicating a less mature neuromotor system. In contrast, L3 larvae show efficient initiation and propagation of neural activity along the entire ventral nerve cord (VNC), resulting in longer activity chains. The time of chain propagation along the entire VNC is shorter in L1 than in L3, probably reflecting the increased length of the VNC. On the other hand, the time of peristaltic waves through the whole body during locomotion is much faster in L3 than in L1, so correlating with higher velocities and greater dispersal rates. Hence, the VNC-body interaction determines the characteristics of peristaltic waves propagation in crawling larvae. Further, asymmetrical neuronal activity, predominantly in anterior segments of L3 larvae, was associated with turning behaviors and enhanced navigation. These findings illustrate that the proposed quantitative model provides a systematic method to analyze neuromotor patterns across developmental stages, for instance, helping to uncover the maturation stages of neural circuits and their role in locomotion. |
| Rachad, E. Y., Deimel, S. H., Epple, L., Gadgil, Y. V., Jurgensen, A. M., Springer, M., Lin, C. H., Nawrot, M. P., Lin, S., Fiala, A. (2025). Functional dissection of a neuronal brain circuit mediating higher-order associative learning. Cell Rep, 44(5):115593 PubMed ID: 40249705
Summary: A central feature characterizing the neural architecture of many species' brains is their capacity to form associative chains through learning. In elementary forms of associative learning, stimuli coinciding with reward or punishment become attractive or repulsive. Notably, stimuli previously learned as attractive or repulsive can themselves serve as reinforcers, establishing a cascading effect whereby they become associated with additional stimuli. When this iterative process is perpetuated, it results in higher-order associations. This study used odor conditioning in Drosophila and computational modeling to dissect the architecture of neuronal networks underlying higher-order associative learning. The responsible circuit, situated in the mushroom bodies of the brain, is characterized by parallel processing of odor information and by recurrent excitatory and inhibitory feedback loops that empower odors to gain control over the dopaminergic valence-signaling system. These findings establish a paradigmatic framework of a neuronal circuit diagram enabling the acquisition of associative chains. | Tadres, D., Riedl, J., Eden, A., Bontempo, A. E., Lin, J., Reid, S. F., Roehrich, B., Williams, K., Sepunaru, L., Louis, M. (2025). Sensation of electric fields in the Drosophila melanogaster larva. Curr Biol, 35(8):1848-1860.e1844 PubMed ID: 40174584
Summary: Electrosensation has emerged as a crucial sensory modality for social communication, foraging, and predation across the animal kingdom. However, its presence and functional role as well as the neural basis of electric field perception in Drosophila and other invertebrates remain unclear. In environments with controlled electric fields, this study identified electrosensation as a new sense in the Drosophila melanogaster larva. The Drosophila larva performs robust electrotaxis: when exposed to a uniform electric field, larvae migrate toward the cathode (negatively charged elecrode) and quickly respond to changes in the orientation of the field to maintain cathodal movement. Through a behavioral screen, a subset of sensory neurons located at the tip of the larval head was identified that are necessary for electrotaxis. Calcium imaging revealed that a pair of Gr66a-positive sensory neurons (one on each side of the head) encodes the strength and orientation of the electric field. These results indicate that electric fields elicit robust behavioral and neural responses in the Drosophila larva, providing new evidence for the significance of electrosensation in invertebrates. |
| Nhuchhen Pradhan, R., Montell, C., Lee, Y. (2025). Cholesterol taste avoidance in Drosophila melanogaster. Elife, 14 PubMed ID: 40244888
Summary: The question as to whether animals taste cholesterol taste is not resolved. This study investigates whether the fruit fly, Drosophila melanogaster, is capable of detecting cholesterol through their gustatory system. Flies were found to be indifferent to low levels of cholesterol and avoid higher levels. The avoidance is mediated by gustatory receptor neurons (GRNs), demonstrating that flies can taste cholesterol. The cholesterol-responsive GRNs comprise a subset that also responds to bitter substances. Cholesterol detection depends on five ionotropic receptor (IR) family members, and disrupting any of these genes impairs the flies' ability to avoid cholesterol. Ectopic expressions of these IRs in GRNs reveals two classes of cholesterol receptors, each with three shared IRs and one unique subunit. Additionally, expressing cholesterol receptors in sugar-responsive GRNs confers attraction to cholesterol. This study reveals that flies can taste cholesterol, and that the detection depends on IRs in GRNs. | Mathada, J. H., Romrig, L., Poissonnier, L. A. (2025). Single-trial learning leads to mid-term memory formation in ants during an appetitive, but not an aversive, task. Proc Biol Sci, 292(2045):20243054 PubMed ID: 40262645
Summary: Insects have been models of associative learning and its underlying memory mechanisms. Research on the fruit fly Drosophila melanogaster and the honeybee Apis mellifera yielded deep insights into the different memory types and their formation dynamics following repeated stimulus exposure. However, less is understood about the ability of insects to learn from a single exposure. Accumulating evidence reveals that several insect species are able to learn from a single trial. Studies have largely focused on odour appetitive learning. In this study, we investigated the ability of the ant Lasius niger to learn from a single trial to associate a reward or a punishment with one side of a Y-maze. The ants successfully demonstrated appetitive learning but no aversive learning. This appetitive learning led to the rapid formation of mid-term memory, remaining sensitive to anaesthesia for at least 15 min post-training. Contrary to single-trial appetitive odour learning described in other species, this learning did not induce the formation of long-term memory, calling for further comparison between learning types. |
Monday March 9th - Physiology and Metabolism |
| Novikov, B., Boland, D. J., Mertsalov, I., Scott, H., Dauletbayeva, S., Monagas-Valentin, P., Panin, V. (2025). CMP-sialic acid synthetase in Drosophila requires N-glycosylation of a noncanonical site. J Biol Chem, 301(6):108483 PubMed ID: 40204091
Summary: Sialylation plays important roles in animals, affecting numerous molecular and cell interactions. In Drosophila, sialylation regulates neural transmission and mediates communication between neurons and glia. Drosophila CMP-sialic acid synthetase (CSAS), a key enzyme of the sialylation pathway, is localized to the Golgi and modified by N-glycosylation, suggesting that this modification can affect CSAS function. This hypothesis was tested using in vitro and in vivo approaches. CSAS proteins from divergent Drosophila species were found to have two conserved N-glycosylation sites, including the rarely glycosylated noncanonical N-X-C sequon. CSAS glycosylation was investigated by generating CSAS "glycomutants" lacking glycosylation sites and these were analyzed in vivo in transgenic rescue assays. The removal of noncanonical glycosylation significantly decreased CSAS activity, while the canonical site mutation did not affect CSAS function. Although all glycomutants were similarly localized to the Golgi, the non-canonical glycosylation, unlike the canonical one, affected CSAS stability in vivo and in vitro. These results suggested that CSAS functions as a dimer, which was also supported by protein structure predictions that produced a dimer recapitulating the crystal structures of mammalian and bacterial counterparts, highlighting the evolutionary conservation of the CSAS structure-function relationship. This conclusion was supported by the rescue of CSAS mutants using the human ortholog. The noncanonical CSAS glycosylation was discussed in terms of a potential mechanism of temperature-dependent regulation of sialylation in poikilotherms that modulates neural activity in heat shock conditions. Taken together, this study uncovered an important regulation of sialylation in Drosophila, highlighting a novel interplay between glycosylation pathways in neural regulation. | Singh, A. S., Pathak, D., Jain, S., Devi, M. S., Nongthomba, U. (2025). Evaluating the potential toxicity of ampicillin using Drosophila melanogaster as a model organism. Toxicol Rep, 14:101992 PubMed ID: 40206788
Summary: Antibiotic resistance is an indispensable threat facing in the present era. However, the studies on long term and trans-generational effects of using drugs or antibiotics on living organisms are scarce. Emphasizing the necessity to address such problems, this study investigated the potential effects of antibiotic, ampicillin (AMP) stress on the physiology of Drosophila melanogaster across multiple generations with mechanistic details. The larval feeding behavior, fertility, cell viability in ovary and testis, longevity, expression of methylation-related genes (dDnmt2 and dMBD2/3), and antimicrobial peptide production were evaluated. Larvae exposed to AMP exhibited increased mouth hook movement, indicating altered behaviour. AMP stress significantly reduced fertility across generations, with eclosion counts decreasing notably in F(3) and F(4) generations compared to controls. Moreover, AMP-treated flies showed decreased cell viability in ovary and testis, leading to impaired reproductive function. AMP exposure shortened the mean lifespan of flies and upregulated the expression of apoptosis-related gene p53 in females. However, there was no significant difference in p53 expression in males. Additionally, AMP stress caused a significant decrease in Drosomycin expression in treated males, while no significant changes were observed in Drosocin and Metchnikowin. In treated females, Drosocin and Drosomycin expression increased significantly, whereas the increase in Metchnikowin was not significant. The study also revealed downregulation of methylation-related genes (dDnmt2 and dMBD2/3) in AMP-treated female flies which was normalised in the rescue flies suggesting disrupted epigenetic mechanisms. Overall, the findings highlighted the importance of evaluating the trans-generational impacts of AMP stress on Drosophila physiology and gene expression, particularly in reproductive function and epigenetic regulation. The study of the impact of widely used antibiotic, AMP on model organism, Drosophila (model organism known for its genetic similarity to human), will help in predicting potential impacts on higher organisms and human. The finding would ultimately promote proper use of antibiotics and use of alternative medicine. |
| Nedbalova, P., Kaislerova, N., Chodakova, L., Moos, M., Doleaal, T. (2025). SAM transmethylation pathway and adenosine recycling to ATP are essential for systemic regulation and immune response. Elife, 13 PubMed ID: 40193491
Summary: During parasitoid wasp infection, activated immune cells of Drosophila melanogaster larvae release adenosine to conserve nutrients for immune response. S-adenosylmethionine (SAM) is a methyl group donor for most methylations in the cell and is synthesized from methionine and ATP. After methylation, SAM is converted to S-adenosylhomocysteine, which is further metabolized to adenosine and homocysteine. This study shows that the SAM transmethylation pathway is up-regulated during immune cell activation and that the adenosine produced by this pathway in immune cells acts as a systemic signal to delay Drosophila larval development and ensure sufficient nutrient supply to the immune system. This study further showed that the up-regulation of the SAM transmethylation pathway and the efficiency of the immune response also depend on the recycling of adenosine back to ATP by adenosine kinase and adenylate kinase. We therefore hypothesize that adenosine may act as a sensitive sensor of the balance between cell activity, represented by the sum of methylation events in the cell, and nutrient supply. If the supply of nutrients is insufficient for a given activity, adenosine may not be effectively recycled back into ATP and may be pushed out of the cell to serve as a signal to demand more nutrients. | Nath, D. K., Dhakal, S. and Lee, Y. (2025). TRPγ regulates lipid metabolism through Dh44 neuroendocrine cells. Elife, 13 PubMed ID: 40243537
Summary: Understanding how the brain controls nutrient storage is pivotal. Transient receptor potential (TRP) channels are conserved from insects to humans. They serve in detecting environmental shifts and in acting as internal sensors. Previous work demonstrated the role of TRPγ in nutrient-sensing behavior. This study found that a TRPγ mutant exhibited in Drosophila melanogaster is required for maintaining normal lipid and protein levels. In animals, lipogenesis and lipolysis control lipid levels in response to food availability. Lipids are mostly stored as triacylglycerol in the fat bodies (FBs) of D. melanogaster. Interestingly, trpγ deficient mutants exhibited elevated TAG levels and genetic data indicated that Dh44 neurons (for information on Dh44 neurons, go to Google and enter Dh44 neurons Drosophila) are indispensable for normal lipid storage but not protein storage. The trpγ mutants also exhibited reduced starvation resistance, which was attributed to insufficient lipolysis in the FBs. This could be mitigated by administering lipase or metformin orally, indicating a potential treatment pathway. Gene expression analysis indicated that trpγ knockout downregulated brummer, a key lipolytic gene, resulting in chronic lipolytic deficits in the gut and other fat tissues. The study also highlighted the role of specific proteins, including neuropeptide DH44 and its receptor DH44R2 in lipid regulation. These findings provide insight into the broader question of how the brain and gut regulate nutrient storage. |
| Ratnawati, R., Aswad, M., Jumriani, J., Nurhidayah, A., Azmin, M. R., Filmaharani, F., Roosevelt, A., Hardiyanti, W., Latada, N. P., Mudjahid, M., Nainu, F. (2025). In Silico and In Vivo Investigation of the Anti-Hyperglycemic Effects of Caffeic Acid. ACS Omega, 10(14):14052-14062 PubMed ID: 40256540
Summary: Hyperglycemia, characterized by elevated blood glucose levels, is a major risk factor for diabetes mellitus and its complications. While conventional therapies are effective, they are often associated with side effects and high costs, necessitating alternative strategies. This study evaluates the potential of caffeic acid (CA), a phenolic compound with reported antihyperglycemic properties, using both in silico and in vivo approaches. Molecular docking simulations revealed that CA demonstrates a strong binding affinity to protein tyrosine phosphatase 1B (PTP1B), a critical enzyme in glucose metabolism, with superior interaction profiles compared to the reference drug, ertiprotafib. In the in vivo studies, a Drosophila melanogaster model was used to investigate the effects of CA under hyperglycemic conditions induced by a high-sugar diet. Treatment with CA, particularly at a concentration of 500 μM, significantly reduced hemolymph glucose levels and improved several physiological and behavioral parameters, including survival rates, body size, body weight, and larval movement. Furthermore, gene expression analysis demonstrated that CA modulates key metabolic and stress-related pathways, enhancing glucose homeostasis and reducing metabolic stress. These findings highlight the dual utility of in silico and in vivo methodologies in elucidating the antihyperglycemic potential of CA. The results support the development of CA as a cost-effective and ethically viable therapeutic candidate with implications for diabetes management in resource-limited settings. | Pimentel, A. C., Cesar, C. S., Martins, A. H. B., Martins, M., Cogni, R. (2025). Wolbachia Offers Protection Against Two Common Natural Viruses of Drosophila. Microb Ecol. 88(1):24
88(1):24. PubMed ID: 40202691
Summary: Wolbachia pipientis is a maternally transmitted endosymbiont infecting more than half of terrestrial arthropod species. Wolbachia can express parasitic phenotypes such as manipulation of host reproduction and mutualist phenotypes such as protection against RNA virus infections. Because Wolbachia can invade populations by reproductive manipulation and block virus infection, it is used to modify natural insect populations. However, the ecological importance of virus protection is not yet clear, especially due to scarce information on Wolbachia protection against viruses that are common in nature. This study used systemic infection to investigate whether Wolbachia protects its host by suppressing the titer of DMELDAV and DMelNora virus, two viruses that commonly infect Drosophila melanogaster flies in natural populations. Antiviral protection was tested in three systems to assess the impact of Wolbachia strains across species: (1) a panel of Wolbachia strains transfected into Drosophila simulans, (2) two Wolbachia strains introgressed into the natural host D. melanogaster, and (3) two native Wolbachia strains in their natural hosts Drosophila baimaii and Drosophila tropicalis. Certain Wolbachia strains were shown to provide protection against DMelNora virus and DMELDAV, and this protection is correlated with Wolbachia density, which is consistent with what has been observed in protection against other RNA viruses. Additionally, Wolbachia does not protect its original host, D. melanogaster, from DMELDAV infection. While native Wolbachia can reduce DMELDAV titers in D. baimaii, this effect was not detected in D. tropicalis. Although the Wolbachia protection-induced phenotype seems to depend on the virus, the specific Wolbachia strain, and the host species, these findings suggest that antiviral protection may be one of the mutualistic effects that helps explain why Wolbachia is so widespread in arthropod populations. |
Friday March 7th - Disease Models |
| Roy, P. R., Link, N. (2025). Loss of Neuronal Imp Contributes to Seizure Behavior through Syndecan Function. eNeuro, 12(5) PubMed ID: 40258646
Summary: Seizures affect a large proportion of the global population and occur due to abnormal neuronal activity in the brain. Unfortunately, widespread genetic and phenotypic heterogeneity contributes to insufficient treatment options. It is critical to identify the genetic underpinnings of how seizures occur to better understand seizure disorders and improve therapeutic development. The Drosophila melanogaster model was used to identify that IGF-II mRNA-binding protein (Imp) is linked to the onset of this phenotype. Specific reduction of Imp in neurons causes seizures after mechanical stimulation. Importantly, gross motor behavior is unaffected, showing Imp loss does not affect general neuronal activity. Developmental loss of Imp is sufficient to cause seizures in adults; thus, Imp-modulated neuron development affects mature neuronal function. Since Imp is an RNA-binding protein, this study sought to identify the mRNA target that Imp regulates in neurons to ensure proper neuronal activity after mechanical stress. Imp protein was found to bind Syndecan (Sdc) mRNA, and the reduction of Sdc also causes mechanically induced seizures. Expression of Sdc in Imp-deficient neurons rescues seizure defects, showing that Sdc is sufficient to restore normal behavior after mechanical stress. It is suggested that the Imp protein binds Sdc mRNA in neurons, and this functional interaction is important for normal neuronal biology and animal behavior in a mechanically induced seizure model. Since Imp and Sdc are conserved, this work highlights a neuronal-specific pathway that might contribute to seizure disorder when mutated in humans. | Pech, U., Janssens, J., Schoovaerts, N., Kuenen, S., Calatayud Aristoy, C., Gallego, S. F., Makhzami, S., Hulselmans, G. J., Poovathingal, S., Davie, K., Bademosi, A. T., Swerts, J., Vilain, S., Aerts, S., Verstreken, P. (2025). Synaptic deregulation of cholinergic projection neurons causes olfactory dysfunction across five fly Parkinsonism models. Elife, 13 PubMed ID: 40178224
Summary: The classical diagnosis of Parkinsonism is based on motor symptoms that are the consequence of nigrostriatal pathway dysfunction and reduced dopaminergic output. However, a decade prior to the emergence of motor issues, patients frequently experience non-motor symptoms, such as a reduced sense of smell (hyposmia). The cellular and molecular bases for these early defects remain enigmatic. To explore this, a new collection of five fruit fly models of familial Parkinsonism was developed, and single-cell RNA sequencing was conducted on young brains of these models. Interestingly, cholinergic projection neurons are the most vulnerable cells, and genes associated with presynaptic function are the most deregulated. Additional single nucleus sequencing of three specific brain regions of Parkinson's disease patients confirms these findings. Indeed, the disturbances lead to early synaptic dysfunction, notably affecting cholinergic olfactory projection neurons crucial for olfactory function in flies. Correcting these defects specifically in olfactory cholinergic interneurons in flies or inducing cholinergic signaling in Parkinson mutant human induced dopaminergic neurons in vitro using nicotine, both rescue age-dependent dopaminergic neuron decline. Hence, this research uncovers that one of the earliest indicators of disease in five different models of familial Parkinsonism is synaptic dysfunction in higher-order cholinergic projection neurons and this contributes to the development of hyposmia. Furthermore, the shared pathways of synaptic failure in these cholinergic neurons ultimately contribute to dopaminergic dysfunction later in life. |
| Okonta, C., Ogunyemi, O. M., Olabuntu, B., Abolaji, A. O. (2025). Ameliorative role of naringenin in MPTP- induced Parkinsonism: Insights from Drosophila melanogaster experimental model combined with computational biology. Toxicol Rep, 14:102004 PubMed ID: 40213420
Summary: This study probed the ameliorative effects of naringenin in a D. melanogaster model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism, incorporating computational analysis. Initially, flies were treated with naringenin (100-500 μM) and MPTP (250-750 μM) for 14 days in two separate studies to determine the optimum concentrations for the treatments. Following this, optimum naringenin concentrations (100 and 300 μM) were administered to MPTP (500 μM)-exposed flies in a 4-day study. Motor function, survival rate, and neurotoxicity biomarkers were assessed alongside biological network analysis and molecular docking simulation. Results indicate that naringenin exhibits hormetic behavior, with 100-300 μM providing optimal neuroprotection. The treatments significantly improved negative geotaxis and acetylcholinesterase activity, and reduced MPTP-induced oxidative stress as indicated by reduced nitric oxide, hydrogen peroxide, and protein carbonyl levels. Furthermore, naringenin restored thiol contents, and enhanced catalase and glutathione-S-transferase activities. Network analysis helped to identify key targets, including DRD4, DRD2, NFKB1, MAOB, MAPK14, and CYP2A6, which function in dopaminergic signaling and oxido-inflammatory pathways. Molecular docking analysis revealed strong binding interactions of naringenin with DRD2, MAO, MAPK, and NF-kappaB protein targets, primarily through hydrogen bonding and hydrophobic interactions. Overall, these findings suggest that naringenin mitigates MPTP-induced neurotoxicity by enhancing dopaminergic neurotransmission and suppressing oxidative stress and inflammation. This study further supports the neuroprotective potential of naringenin and could be suggested as a promising nutraceutical/drug candidate for Parkinson's disease. | Mok, J. W., Mackay, L., Blazo, M., Mizerik, E., Gecz, J., Carroll, R., Nizon, M., Rondeau, S., Joubert, M., Cuinat, S., Deb, W., Valle Sirias, F., Weisz-Hubshman, M., Ketkar, S., Polak, U., Tran, A. A., Kearney, D., Hanchard, N. A., Kanca, O., Wangler, M. F., Bellen, H. J., Lee, B. H., Yamamoto, S., Machol, K. (2025). C-terminal frameshift variants in GPKOW are associated with a multisystemic X-linked disorder. Genet Med, 27(7):101429 PubMed ID: 40221893
Summary: GPKOW, a gene on the X-chromosome, encodes a nuclear RNA-binding protein important in messenger RNA (mRNA) processing as a spliceosome subunit. This work aims to establish GPKOW as a disease-associated gene. 3 males from 2 unrelated families are described with hemizygous frameshift variants affecting the last exon of GPKOW p.(Arg441SerfsTer30) and p.(Ser444GlufsTer28). The effect of p.(Ser444GlufsTer28) on gene expression was evaluated in patient's fibroblasts. In vivo studies in Drosophila melanogaster targeting the sole GPKOW fly ortholog, CG10324 (Gpkow) were performed. Clinical presentations included intrauterine growth restriction, microcephaly/microencephaly, and eye, brain, skin, and skeletal abnormalities. Heterozygote females presented with short stature, microcephaly, and vision problems. Sequencing of fibroblasts' mRNA confirmed that GPKOW mRNA escapes nonsense-mediated decay. Yet, reduced protein levels suggested protein instability. Studies in Drosophila showed that Gpkow is essential and broadly expressed. It is enriched in neurons and glia in eyes and head of developing and adult flies. Knockdown and overexpression of Gpkow in the fly eye cause eyeless/headless phenotype, suggesting that the gene is dosage sensitive. Importantly, overexpression of the p.(Ser444GlufsTer28) variant caused milder defects than the reference allele, indicating that the truncated protein behaves as a partial loss-of-function allele. It is concluded that variants in GPKOW cause a multisystemic X-linked syndrome. |
| Shen, D., Vincent, A., Udine, E., Buhidma, Y., Anoar, S., Tsintzas, E., Maeland, M., Xu, D., Carcole, M., Osumi-Sutherland, D., Aleyakpo, B., Hull, A., Martinez Corrales, G., Woodling, N., Rademakers, R., Isaacs, A. M., Frigerio, C., van Blitterswijk, M., Lashley, T., Niccoli, T. (2025). Differential neuronal vulnerability to C9orf72 repeat expansion driven by Xbp1-induced endoplasmic reticulum-associated degradation. Cell Rep, 44(4):115459 PubMed ID: 40203833
Summary: Neurodegenerative diseases are characterized by the localized loss of neurons. Why cell death is triggered only in specific neuronal populations and whether it is the response to toxic insults or the initial cellular state that determines their vulnerability is unknown. To understand individual cell responses to disease, their transcriptional signatures were profiled throughout disease development in a Drosophila model of C9orf72 (G4C2) repeat expansion (C9), the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. Neuronal populations were identified specifically vulnerable or resistant to C9 expression; and an upregulation of protein homeostasis pathways was found in resistant neurons at baseline. Overexpression of Xbp1s, a key regulator of the unfolded protein response and a central node in the resistance network, rescues C9 toxicity. This study shows that neuronal vulnerability depends on the intrinsic transcriptional state of neurons and that leveraging resistant neurons' properties can boost resistance in vulnerable neurons. | Mohar, N. P., Langland, C. J., Darr, Z., Viles, J., Moore, S. A., Darbro, B. W., Wallrath, L. L. (2025). A genetic variant in SMAD7 acts as a modifier of LMNA-associated muscular dystrophy, implicating SMAD signaling as a therapeutic target. Sci Adv, 11(16):eads7903 PubMed ID: 40249815
Summary: Mutations in LMNA cause multiple types of muscular dystrophy (LMNA-MD). The symptoms of LMNA-MD are highly variable and sensitive to genetic background. To identify genetic contributions to this phenotypic variability, whole-genome sequencing was performed on four siblings possessing the same LMNA mutation with differing degrees of skeletal muscle disease severity. A variant in SMAD7 was identified that segregated with severe muscle disease. To functionally test the SMAD7 variant, a Drosophila model was generated possessing the LMNA mutation and the SMAD7 variant in the orthologous fly genes. The SMAD7 variant increased SMAD signaling and enhanced muscle defects caused by the mutant lamin. Conversely, overexpression of wild-type SMAD7 rescued muscle function. These findings were extended to humans by showing that SMAD signaling is increased in muscle biopsy tissue from individuals with LMNA-MD compared to age-matched controls. Collectively, these findings support SMAD7 as the first functionally tested genetic modifier for LMNA-MD and suggest components of the SMAD pathway as therapeutic targets. |
Thursday March 5th - RNAs, RNA interference, Splicing |
| Kawaguchi, S., Xu, X., Soga, T., Yamaguchi, K., Kawasaki, R., Shimouchi, R., Date, S., Kai, T. (2025). In silico screening by AlphaFold2 program revealed the potential binding partners of nuage-localizing proteins and piRNA-related proteins. Elife, 13 PubMed ID: 40259744
Summary: Protein-protein interactions are fundamental to understanding the molecular functions and regulation of proteins. Despite the availability of extensive databases, many interactions remain uncharacterized due to the labor-intensive nature of experimental validation. This study, utilized the AlphaFold2 program to predict interactions among proteins localized in the nuage, a germline-specific non-membrane organelle essential for piRNA biogenesis in Drosophila. 20 nuage proteins were screened for 1:1 interactions and predicted dimer structures. Among these, five represented novel interaction candidates. Three pairs, including Spn-E_Squ, were verified by co-immunoprecipitation. Disruption of the salt bridges at the Spn-E_Squ interface confirmed their functional importance, underscoring the predictive model's accuracy. This analysis was extended to include interactions between three representative nuage components-Vas, Squ, and Tej-and approximately 430 oogenesis-related proteins. Co-immunoprecipitation verified interactions for three pairs: Mei-W68_Squ, CSN3_Squ, and Pka-C1_Tej. Furthermore, the majority of Drosophila proteins (~12,000) was screened for potential interaction with the Piwi protein, a central player in the piRNA pathway, identifying 164 pairs as potential binding partners. This in silico approach not only efficiently identifies potential interaction partners but also significantly bridges the gap by facilitating the integration of bioinformatics and experimental biology. | Gao, S. Y., Lu, H. G., Wang, Y. H., Yan, D. (2025). Screening of Drosophila melanogaster RNA m(6)A modification pathway factors. Journal and Yi Chuan, 47(4):476-488 PubMed ID: 40204521
Summary: N(6)-methyladenosine (m(6)A), one of the most prevalent mRNA modifications, plays crucial roles during animal and plant development and in various physiological and pathological processes. Previous studies have characterized m(6)A methyltransferase complexes, demethylases, and m(6)A-binding proteins, but as a relatively new epitranscriptomic pathway, it is likely that new m(6)A components remain to be discovered. To explore the effects of m(6)A modification on tissues and organs, the m(6)A reader Ythdc1 was overexpressed in Drosophila melanogaster eye imaginal discs. The results showed that overexpression of Ythdc1 leads to ectopic expression of Sxl in males, the rough eye in both males and females, and the activation of JNK signaling and apoptotic pathway. In order to screen m(6)A modifiers using the rough eye phenotype, a stable Drosophila strain overexpressing Ythdc1 was further constructed. By screening of more than 1,500 RNAi lines, several repressors and enhancers that may be involved in m(6)A modification were successfully identified. These genes are less studied in m(6)A pathway, and therefore they were further verified and preliminary mechanistic analyses on them was conducted. In summary, this study identified multiple potential factors of the m(6)A modification pathway, expanded understanding of the m(6)A modification network, and provided ideas and directions for exploring new regulatory mechanisms of this important pathway. |
| Rivera, A. J., Lee, J. R., Gupta, S., Yang, L., Goel, R. K., Zaia, J., Lau, N. C. (2025). Traffic Jam activates the Flamenco piRNA cluster locus and the Piwi pathway to ensure transposon silencing and Drosophila fertility. Cell Rep, 44(4):115354 PubMed ID: 40209716
Summary: Flamenco (Flam) is a prominent Piwi-interacting RNA (piRNA) locus expressed in Drosophila ovarian follicle cells that silences gypsy/mdg4 transposons to ensure female fertility. Promoter-bashing reporter assays in ovarian somatic sheet (OSS) cells uncover compact enhancer sequences within Flam. The enhancer sequence relevance was confirmed in vivo with Drosophila Flam deletion mutants that compromise Flam piRNA levels and female fertility. Proteomic analysis of proteins associated with Flam enhancer sequences discover the transcription factor Traffic Jam (TJ). Tj knockdown in OSS cells causes a decrease in Flam transcripts, Flam piRNAs, and multiple Piwi pathway genes. TJ chromatin immunoprecipitation sequencing (ChIP-seq) analysis confirms TJ binding at enhancer sequences deleted in the distinct Flam mutants. TJ also binds multiple Piwi pathway gene enhancers and long terminal repeats of transposons that decrease in expression after Tj knockdown. TJ plays an integral role in the ongoing arms race between selfish transposons and their suppression by the host Piwi pathway and Flam piRNA locus. | Lee, S. K., Shen, W., Wen, W., Joo, Y., Xue, Y., Park, A., Qiang, A., Su, S., Zhang, T., Zhang, M., Fan, J., Zhang, Y., De, S., Gainetdinov, I., Sharov, A., Maragkakis, M., Wang, W. (2025). Topoisomerase 3b facilitates piRNA biogenesis to promote transposon silencing and germ cell development. Cell Rep, 44(4):115495 PubMed ID: 40184251
Summary: Topoisomerases typically function in the nucleus to relieve topological stress in DNA. This study shows that a dual-activity topoisomerase, Top3b, and its partner, TDRD3, largely localize in the cytoplasm and interact biochemically and genetically with PIWI-interacting RNA (piRNA) processing enzymes to promote piRNA biogenesis, post-transcriptional gene silencing (PTGS) of transposons, and Drosophila germ cell development. Top3b requires its topoisomerase activity to promote PTGS of a transposon reporter and preferentially silences long and highly expressed transposons, suggesting that RNAs with these features may produce more topological stress for topoisomerases to solve. The double mutants between Top3b and piRNA processing enzymes exhibit stronger disruption of the signatures and levels of germline piRNAs, more de-silenced transposons, and larger defects in germ cells than either single mutant. These data suggest that Top3b can act in an RNA-based process-piRNA biogenesis and PTGS of transposons-and this function is required for Top3b to promote normal germ cell function. |
| Alizada, A., Martins, A., Mouniee, N., Rodriguez Suarez, J. V., Bertin, B., Gueguen, N., Mirouse, V., Papameletiou, A. M., Rivera, A. J., Lau, N. C., Akkouche, A., Maupetit-Méhouas, S., Hannon, G. J., Czech Nicholson, B., Brasset, E. (2025). The transcription factor Traffic jam orchestrates the somatic piRNA pathway in Drosophila ovaries. Cell Rep, 44(4):115453 PubMed ID: 40209715
Summary: The PIWI-interacting RNA (piRNA) pathway is essential for transposable element (TE) silencing in animal gonads. While the transcriptional regulation of piRNA pathway components in germ cells has been documented in mice and flies, their control in somatic cells of Drosophila ovaries remains unresolved. This study demonstrates that Traffic jam (Tj), the Drosophila ortholog of large Maf transcription factors in mammals, is a master regulator of the somatic piRNA pathway. Tj binds to regulatory regions of somatic piRNA factors and the major piRNA cluster flamenco, which carries a Tj-bound enhancer downstream of its promoter. Depletion of Tj in somatic follicle cells causes downregulation of piRNA factors, loss of flamenco expression, and derepression of gypsy-family TEs. It is proposed that the arms race between the host and TEs led to the co-evolution of promoters in piRNA pathway genes as well as TE regulatory regions, which both rely on a shared transcription factor. | Soldatova, I. V., Beginyazova, O., Georgiev, P. G., Tikhonov, M. V. (2025). Investigation of the Functional Role of the Conserved Sequence at the 5'-End of the Fourth Intron of the mod(mdg4) Gene in Trans-Splicing in Drosophila melanogaster. Dokl Biochem Biophys, 521(1):169-173 PubMed ID: 40216715
Summary: Alternative splicing is an important mechanism that provides genetic diversity of proteins. Unique loci have been identified in Drosophila melanogaster, where mRNA diversity arises as a result of trans-splicing-a process in which exons from different pre-mRNAs are joined together. The trans-splicing in the mod(mdg4) locus, which encodes more than 31 isoforms, has been studied in detail. Important elements for this process include previously described conserved sequences in the fourth intron. The aim of this study is to further characterize the conserved motifs of the fourth intron, specifically the element at the 5'-end of the intron. Using model transgenic lines, it has been shown that introduced changes in the sequence of the studied element lead to a disruption of trans-splicing. In contrast, similar changes in the endogenous locus did not result in a disruption of trans-splicing. Thus, the conserved element plays a role in trans-splicing but is not critical. |
Wednesday March 4th - Tumors and Growth |
| Rai, M., Okah, P., Shefali, S. A., Fitt, A. J., Shen, M. Z., Molomjamts, M., Pepin, R., Nemkov, T., D'Alessandro, A., Tennessen, J. M. (2025). New alleles of D-2-hydroxyglutarate dehydrogenase enable studies of oncometabolite function in Drosophila melanogaster. bioRxiv, PubMed ID: 40236175
Summary: D-2-hydroxyglutarate (D-2HG) is a potent oncometabolite capable of disrupting chromatin architecture, altering metabolism, and promoting cellular dedifferentiation. As a result, ectopic D-2HG accumulation induces neurometabolic disorders and promotes progression of multiple cancers. However, the disease-associated effects of ectopic D-2HG accumulation are dependent on genetic context. Specifically, neomorphic mutations in the mammalian genes Isocitrate dehydrogenase 1 (IDH1) and IDH2 result in the production of enzymes that inappropriately generate D-2HG from α-ketoglutarate (αKG). Within this genetic background, D-2HG acts as an oncometabolite and is associated with multiple cancers, including several diffuse gliomas. In contrast, loss-of-function mutations in the gene D-2-hydroxyglutarate dehydrogenase (D2hgdh) render cells unable to degrade D-2HG, resulting in excessive buildup of this molecule. D2hgdh mutations, however, are not generally associated with elevated cancer risk. This discrepancy raises the question as to why ectopic D-2HG accumulation in humans induces context-dependent disease outcomes. To enable such genetic studies in vivo, two novel loss-of-function mutations were generated in the Drosophila melanogaster gene "http://flybase.org/reports/FBgn0023507">D2hgdh, and these alleles result in ectopic D-2HG. Moreover, it was observed that D2hgdh mutations induce developmental and metabolomic phenotypes indicative of elevated D-2HG accumulation. Overall, these efforts provide the Drosophila community with new mutant strains that can be used to study D-2HG function in human disease models as well as in the context of normal growth, metabolism, and physiology. | Dillard, C., Teles-Reis, J., Jain, A., Antunes, M. G., Ruiz-Duran, P., Qi, Y., Le Borgne, R., Jasper, H., Rusten, T. E. (2025). NF-kappaB signaling driven by oncogenic Ras contributes to tumorigenesis in a Drosophila carcinoma model.. PLoS Biol, 23(4):e3002663 PubMed ID: 40294135
Summary: Cancer-driving mutations synergize with inflammatory stress signaling pathways during carcinogenesis. Drosophila melanogaster tumor models are increasingly recognized as models to inform conserved molecular mechanisms of tumorigenesis with both local and systemic effects of cancer. Although initial discoveries of the Toll-NFkappaB signaling pathway in development and immunity were pioneered in Drosophila, limited information is available for its role in cancer progression. Using a well-studied cooperative RasV12-driven epithelial-derived tumor model, this study describes functions of Toll-NF-kappaB signaling in malignant RasV12, scrib- tumors. The extracellular Toll pathway components ModSP and PGRP-SA and intracellular signaling Kinase, Pelle/IRAK, are rate-limiting for tumor growth. The Toll pathway NFkappaB protein Dorsal as well as /IkappaΒ show elevated expression in tumors with highest expression in invasive cell populations. Oncogenic RasV12, and not loss of scribble, confers increased expression and heterogenous distribution of two Dorsal isoforms, DorsalA and DorsalB, in different tumor cell populations. Mechanistic analyses demonstrates that Dorsal, in concert with the BTB-transcription factor Chinmo, drives growth and malignancy by suppressing differentiation, counteracting apoptosis, and promoting invasion of RasV12, scrib- tumors. |
| Li, M., Tian, A., Jiang, J. (2025). Numb provides a fail-safe mechanism for intestinal stem cell self-renewal in adult Drosophila midgut. Journal and Elife, 14 PubMed ID: 40202131
Summary: Stem cell self-renewal often relies on asymmetric fate determination governed by niche signals and/or cell-intrinsic factors but how these regulatory mechanisms cooperate to promote asymmetric fate decision remains poorly understood. In adult Drosophila midgut, asymmetric Notch (N) signaling inhibits intestinal stem cell (ISC) self-renewal by promoting ISC differentiation into enteroblast (EB). Previous work has shown that epithelium-derived Bone Morphogenetic Protein (BMP) promotes ISC self-renewal by antagonizing N pathway activity. This study showed that loss of BMP signaling (Decapentaplegic (Dpp) and Glass bottom boat (Gbb) heterodimers) results in ectopic N pathway activity even when the N ligand Delta (Dl) is depleted, and that the N inhibitor Numb acts in parallel with BMP signaling to ensure a robust ISC self-renewal program. Although Numb is asymmetrically segregated in about 80% of dividing ISCs, its activity is largely dispensable for ISC fate determination under normal homeostasis. However, Numb becomes crucial for ISC self-renewal when BMP signaling is compromised. Whereas neither Mad RNA interference nor its hypomorphic mutation led to ISC loss, inactivation of Numb in these backgrounds resulted in stem cell loss due to precocious ISC-to-EB differentiation. Furthermore, numb mutations resulted in stem cell loss during midgut regeneration in response to epithelial damage that causes fluctuation in BMP pathway activity, suggesting that the asymmetrical segregation of Numb into the future ISC may provide a fail-save mechanism for ISC self-renewal by offsetting BMP pathway fluctuation, which is important for ISC maintenance in regenerative guts. | Church, S. J., Pulianmackal, A. J., Dixon, J. A., Loftus, L. V., Amend, S. R., Pienta, K., Cackowski, F. C., Buttitta, L. A. (2025). Oncogenic signaling in the Drosophila prostate-like accessory gland activates a pro-tumorigenic program in the absence of proliferation. Dis Model Mech, 18(4) PubMed ID: 40304035
Summary: Drosophila models for tumorigenesis have revealed conserved mechanisms of signaling involved in mammalian cancer. Many of these models use highly mitotically active Drosophila tissues. Few Drosophila tumorigenesis models use adult tissues, when most cells are terminally differentiated and postmitotic. The Drosophila accessory glands are prostate-like tissues, and a model for prostate tumorigenesis using this tissue has been explored. In this prior model, oncogenic signaling was induced during the proliferative stages of accessory gland development, raising the question of how oncogenic activity impacts the terminally differentiated, postmitotic adult tissue. This study showed that oncogenic signaling in the adult Drosophila accessory gland leads to activation of a conserved pro-tumorigenic program, similar to that of mitotic tissues, but in the absence of proliferation. In these experiments, oncogenic signaling in the adult gland led to tissue hypertrophy with nuclear anaplasia, in part through endoreduplication. Oncogene-induced gene expression changes in the adult Drosophila prostate-like model overlapped with those in polyploid prostate cancer cells after chemotherapy, which potentially mediate tumor recurrence. Thus, the adult accessory glands provide a useful model for aspects of prostate cancer progression that lack cellular proliferation. |
| Li, J., Taniguchi, K., Ye, W., Kondo, S., Kobayashi, T., Matsuyama, M., Saito, K., Ohsawa, S., Igaki, T. (2025). Epithelial cell-fate switch triggering ectopic ligand-receptor-mediated JAK-STAT signaling promotes tumorigenesis in Drosophila. iScience, 28(4):112191 PubMed ID: 40230533
Summary: Disruption of epithelial architecture is a hallmark of human malignant cancers, yet whether and how epithelial deformation influences tumor progression has been elusive. Through a genetic screen in Drosophila eye disc, this study explored mutations that potently promoted Ras-activated (Ras(V12)) tumor growth and identified eyes absent (eya), an eye determination gene, whose mutation compromised tissue growth but synergized with Ras(V12) to cause massive overgrowth. Furthermore, induction of cell-fate switch by mis-expression of Abd-B in the eye disc also induced massive Ras(V12) overgrowth. Mechanistically, cell-fate switch caused epithelial invagination accompanied by partial mislocalization of the transmembrane receptor Domeless (Dome) from the apical to the basal membrane of the eye epithelium, where its ligand Unpaired3 (Upd3) is present. This led to JAK-STAT activation that cooperates with Ras(V12) to drive tumor progression. These data provide a mechanistic explanation for how cell-fate switch and subsequent epithelial deformation creates a cancer-prone environment in the epithelium. | Wang, Y., Huang, R., Deng, M., He, J., Deng, M., Ishibashi, T., Yu, C., Zhai, Z., Yan, Y. (2025). Oncogenic Ras, Yki and Notch signals converge to confer clone competitiveness through Upd2. J Genet Genomics, PubMed ID: 40320143
Summary: Cell competition is an evolutionarily ancient mechanism that functions to remove unfit or dangerous clonal cells in a multicellular community. A classical model is the removal of polarity-deficient clones, such as the precancerous scribble (scrib) mutant clones, in Drosophila imaginal discs. The activation of Ras, Yki, or Notch signaling robustly reverses the scrib mutant clonal fate from elimination to tumorous growth. Whether these signals converge to adopt a common mechanism to overcome the elimination pressure posed by cell competition remains unclear. Using single-cell transcriptomics, this study found that a critical converging point downstream of Ras, Yki, and Notch signals is the upregulation of Upd2, an IL-6 family cytokine. Overexpression of Upd2 is sufficient to rescue the scrib mutant clones from elimination. Depletion of Upd2 blocks the growth of the scrib mutant clones with active Ras, Yki, and Notch signals. Moreover, Upd2 overexpression promotes robust intestinal stem cell (ISC) proliferation, while Upd2 is intrinsically required in ISCs for the growth of the adult intestine. Together, these results identify Upd2 as a crucial cell fitness factor that sustains tissue growth but can potentiate tumorigenesis when deregulated. |
Tuesday March 3rd - Genes, Enzymes RNA and Protein Expression Evolution Structure and Function |
| Perez-Roldan, J., Henn, L., Bernues, J., Torras, L. M., Tamirisa, S., Belloc, E., Rodriguez-Munoz, L., Timinszky, G., Jimenez, G., Mendez, R., Carbonell, A., Azoran, F. (2025). Maternal histone mRNAs are uniquely processed through polyadenylation in a Stem-Loop Binding Protein (SLBP) dependent manner. Nucleic Acids Res, 53(7) PubMed ID: 40239992
Summary: >During early embryogenesis the zygotic genome remains transcriptionally silent and expression relies on maternally deposited products. Maternal deposition of histones is crucial to preserve chromatin integrity during early embryo development, when the number of nuclei exponentially increases in the absence of zygotic expression. In the Drosophila embryo, histones are maternally deposited as both proteins and mRNAs. Histone transcripts are the only nonpolyadenylated cellular mRNAs. They contain a highly conserved 3'UTR stem-loop structure, which is recognized by the Stem-Loop Binding Protein (SLBP) that, in conjunction small nuclear RNA U7, regulates their unique 3'-end processing. This study reports that, unexpectedly, maternal histone mRNAs are polyadenylated and have a truncated 3' stem-loop. This noncanonical 3'-end processing of maternal histone mRNAs occurs at their synthesis during oogenesis and requires SLBP, but not U7 snRNP. Maternal histone transcripts are subjected to cytoplasmic poly(A) tail elongation by Wisp, which results in their stabilization and is a requisite for translation. Maternal histone transcripts remain largely quiescent, their translation is activated upon loss of the embryonic linker histone dBigH1, which impairs chromatin assembly and induces DNA damage. Possible models to integrate these observations are discussed. | Zukowska, J., Gregory, K. S., Robinson, A., Isaac, R. E., Acharya, K. R. (2025). Molecular Basis of Dipeptide Recognition in Drosophila melanogaster Angiotensin I-Converting Enzyme Homologue, AnCE. Biomolecules, 15(4) PubMed ID: 40305366
Summary: Human angiotensin-I-converting enzyme (ACE) is involved in vasoregulation, inflammation, and neurodegenerative disorders. The enzyme is formed of two domains; the C-domain (cACE) is primarily involved in blood pressure regulation, whereas the N-domain (nACE) is strongly linked to fibrosis; hence, designing domain-specific inhibitors could make a difference between treating one condition without having a negative effect on another. AnCE (a close homologue of ACE) is derived from Drosophila melanogaster and has a high similarity specifically to cACE. Due to high similarity and ease of crystallisation, AnCE has been chosen as a model protein for ACE studies and for the design of ACE inhibitors. In this study, enzyme kinetic assays and X-ray crystallography techniques revealed the significance of using dipeptides as selective inhibitors for AnCE and how this knowledge could be applied to cACE and nACE. All the dipeptides tested in this study were shown to bind AnCE in two distinct locations, i.e., the non-prime and prime subsites. It was found that a hydrophobic residue at the S1 and S1' subsites, with a tryptophan at the S2 and S2' subsites, showed highest affinity towards AnCE. It was also observed that a key pocket within the S2' subsite had a major influence on the binding orientation within the prime subsites and could potentially explain ACE's dipeptidyl carboxypeptidase activity. Importantly these dipeptides are found in functional foods, making them potentially available from diets. Knowledge of the dipeptide binding presented in this study could aid in the development of ACE domain-specific inhibitors. |
| Cheng, Y., Chen, Y. X., Gao, J. N., Chen, J., Huang, J., Qiao, X. (2025). Multiple Mutations in the beta1 Subunit of the Nicotinic Acetylcholine Receptor Confer Resistance to Neonicotinoids. J Agric Food Chem, 73(20):12176-12183 PubMed ID: 40353574
Summary: The evolution of resistance to neonicotinoid insecticides threatens global agriculture. To elucidate its molecular basis, this study employed Drosophila melanogaster as a model system to investigate resistance-associated mutations in the β1 subunit of nicotinic acetylcholine receptors (nAChRs). Using a CRISPR/Cas9-mediated allele replacement, homozygous knock-in mutants (V62I, V101I, R81E, and A60T,R81E) were generated without apparent fitness costs. Toxicity bioassays revealed that these mutations confer varying resistance levels, with the R81E mutation exhibiting over 225-fold resistance to thiamethoxam, clothianidin, and dinotefuran. A heteropentameric α1β1 nAChR model, generated using an AI-based protein-ligand prediction (Chai-1), showed that imidacloprid binds at the orthosteric site, where R81 forms a critical electrostatic interaction. Residues A60, V62, and V101, positioned further from the binding site, showed spatial distances correlated with their resistance ratios. These findings provide genetic and structural insights into neonicotinoid resistance mechanisms, offering a foundation for the design of next-generation insecticides and resistance management strategies. | Kasuya, J., Kruth, K., Lee, D., Kim, J. S., Williams, A., Kitamoto, T. (2025). Effects of lithium on mortality and metabolite profiles in Drosophila lithium-inducible SLC6 transporter mutants. Environ Toxicol Pharmacol, 116:104684 PubMed ID: 40194719
Summary: Lithium has long been the primary treatment for bipolar disorder and shows promise for managing other neurological and psychiatric conditions. The has been identified in Drosophila melanogaster as a gene significantly upregulated in response to lithium chloride supplementation. List encodes a putative amino acid transporter belonging to the Na+-dependent solute carrier family 6. List is expressed in the Malpighian tubules, glia, and hindgut. RNA interference-mediated List knockdown in the Malpighian tubules drastically increases lithium-induced mortality. Additionally, List loss-of-function mutants (ListTG4.2) accumulate six times more internal lithium than controls after lithium exposure. Metabolomic analysis revealed disrupted amino acid metabolism and a shift toward a more oxidized cellular redox state in lithium-treated List(TG4.2) mutants. Overall, these findings suggest that List protects flies from lithium toxicity by regulating internal lithium levels and maintaining metabolic and redox balance. |
| Dean, D. M., Codd, L. E., Constanza, R., Segel, X. M. (2025). purpleoid (1), a classic Drosophila eye color mutation, is an allele of the t-SNARE-encoding gene SNAP29. MicroPubl Biol, 2025 PubMed ID: 40270683
Summary: The Drosophila mutant eye color trait purpleoid (pd) was first observed by Calvin Bridges over a century ago. Although pd mutant strains have been maintained ever since, the pd locus has not been identified. Using complementation tests, genetic rescue, and DNA sequencing, this study showed that pd1 is a missense mutation in SNAP29; this gene encodes a key component of the SNARE complex, which facilitates vesicle docking and fusion at cellular membranes. After describing how pd1 was mapped, ways that the mutation could be used in future studies of eye pigmentation, SNARE complex assembly, and vesicle trafficking, are discussed. | Komp, E., Phillips, C., Lee, L. M., Fallin, S. M., Alanzi, H. N., Zorman, M., McCully, M. E., Beck, D. A. C. (2025). Neural network conditioned to produce thermophilic protein sequences can increase thermal stability. Sci Rep, 15(1):14124 PubMed ID: 40268970
Summary: This work presents Neural Optimization for Melting-temperature Enabled by Leveraging Translation (NOMELT), a novel approach for designing and ranking high-temperature stable proteins using neural machine translation. The model, trained on over 4 million protein homologous pairs from organisms adapted to different temperatures, demonstrates promising capability in targeting thermal stability. A designed variant of the Drosophila melanogaster Engrailed Homeodomain shows a melting temperature increase of 15.5 K. Furthermore, NOMELT achieves zero-shot predictive capabilities in ranking experimental melting and half-activation temperatures across a number of protein families. It achieves this without requiring extensive homology data or massive training datasets as do existing zero-shot predictors by specifically learning thermophilicity, as opposed to all natural variation. These findings underscore the potential of leveraging organismal growth temperatures in context-dependent design of proteins for enhanced thermal stability. |
Thursday February 26th - Chromatin |
| Jayakrishnan, M., Havlova, M., Veverka, V., Regnard, C., Becker, P. B. (2025). Genomic context-dependent histone H3K36 methylation by three Drosophila methyltransferases and implications for dedicated chromatin readers. Nucleic Acids Res, 53(6) PubMed ID: 40164442
Summary: Methylation of histone H3 at lysine 36 (H3K36me3) marks active chromatin. The mark is interpreted by epigenetic readers that assist transcription and safeguard chromatin fiber integrity. In Drosophila, the chromodomain protein MSL3 binds H3K36me3 at X-chromosomal genes to implement dosage compensation. The PWWP-domain protein JASPer recruits the JIL1 kinase to active chromatin on all chromosomes. Because depletion of K36me3 had variable, locus-specific effects on the interactions of those readers,K36 methylation was systematically studied in a defined cellular model. Contrasting prevailing models, K36me1, K36me2, and K36me3 were each found to contribute to distinct chromatin states. Monitoring the changing K36 methylation landscape upon depletion of the three methyltransferases Set2, NSD, and Ash1 revealed local, context-specific methylation signatures. Each methyltransferase governs K36 methylation in dedicated genomic regions, with minor overlaps. Set2 catalyzes K36me3 predominantly at transcriptionally active euchromatin. NSD places K36me2/3 at defined loci within pericentric heterochromatin and on weakly transcribed euchromatic genes. Ash1 deposits K36me1 at putative enhancers. The mapping of MSL3 and JASPer suggested that they bind K36me2 in addition to K36me3, which was confirmed by direct affinity measurement. This dual specificity attracts the readers to a broader range of chromosomal locations and increases the robustness of their actions. | Farmer, A. J., Katariya, R., Islam, S., Rayhan, M. S. A., Inlow, M. H., Ahmad, S. M., Schwab, K. R. (2025). trithorax is an essential regulator of cardiac Hox gene expression and anterior-posterior patterning of the Drosophila embryonic heart tube. Biol Open, 14(4) PubMed ID: 40172069
Summary: The precise regulation of transcription required for embryonic development is partially controlled by the actions of the Trithorax group (TrxG) and Polycomb group (PcG) proteins. The genes trithorax (trx), trithorax-related (trr), and SET domain containing 1 (Set1) encode COMPASS-like histone methyltransferases, a subgroup of TrxG proteins that impart H3K4 methylation modifications onto chromatin in order to activate and maintain transcription. This study identified the role of these genes in the development of the embryonic heart of the fruit fly Drosophila melanogaster. trx, trr, and Set1 independently ensure proper cardiac cell divisions. Additionally, trx regulation of collinear Hox expression is necessary for the anterior-posterior cardiac patterning of the linear heart tube. trx inactivation in Drosophila results in a remarkable homeotic transformation of the posterior heart-proper segment into an aorta-like fate due to the loss of posterior abdominal A expression. Furthermore, cardiac expression of Antennapedia, Ultrabithorax, and Abdominal B is also deregulated in trx mutants. Together, these data suggest that the COMPASS-like histone methyltransferases are essential developmental regulators of cardiogenesis, being necessary for both cardiac cell divisions and heart patterning. |
| Ostale, C. M., Azpiazu, N., Peropadre, A., Martin, M., Ruiz-Losada, M., Lopez-Varea, A., Viales, R. R., Girardot, C., Furlong, E. E. M., de Celis, J. F. (2025). A function of Spalt proteins in heterochromatin organization and maintenance of genomic DNA integrity. Development, 152(10) PubMed ID: 40326666
Summary: The conserved Spalt proteins regulate gene expression and cell fate choices during multicellular development, generally acting as transcriptional repressors in different gene regulatory networks. In addition to their roles as DNA sequence-specific transcription factors, Spalt proteins show a consistent localization to heterochromatic regions. Vertebrate Spalt-like proteins can act through the nucleosome remodeling and deacetylase complex to promote closing of open chromatin domains, but their activities also rely on interactions with DNA methyltransferases or with the lysine-specific histone demethylase LSD1, suggesting that they participate in multiple regulatory mechanisms. This study describes several consequences of loss of Spalt function in Drosophila cells, including changes in chromatin accessibility, generation of DNA damage, alterations in the localization of chromosomes within the nucleus in the salivary glands and misexpression of transposable elements. These effects are thought to be related to roles of Spalt proteins in the regulation of heterochromatin formation and chromatin organization. It is proposed that Drosophila Spalt proteins have two complementary functions, acting as sequence-specific transcriptional repressors on specific target genes and regulating more global gene silencing through the generation or maintenance of heterochromatic domains. | Mouginot, M., Hani, S., Cousin, P., Dorier, J., Ravera, A., Gambetta, M. C. (2025). A boundary-defining protein facilitates megabase-scale regulatory chromosomal loop formation in Drosophila neurons. Genes Dev, 39(11-12):706-726 PubMed ID: 40240144
Summary: Regulatory elements, such as enhancers and silencers, control transcription by establishing physical proximity to target gene promoters. Neurons in flies and mammals exhibit long-range three-dimensional genome contacts, proposed to connect genes with distal regulatory elements. However, the relevance of these contacts for neuronal gene transcription and the mechanisms underlying their specificity necessitate further investigation. This study precisely disrupt several long-range contacts in fly neurons, demonstrating their importance for megabase-range gene regulation was further revealed, and uncovering a hierarchical process in their formation. An essential role for the chromosomal boundary-forming protein Cp190 in anchoring many long-range contacts, highlighting a mechanistic interplay between boundary and loop formation. Finally, an unbiased proteomics-based method was developed to systematically identify factors required for specific long-range contacts. These findings underscore the essential role of architectural proteins such as Cp190 in cell type-specific genome organization in enabling specialized neuronal transcriptional programs. |
| Denaud, S., Sabaris, G., Di Stefano, M., Papadopoulos, G. L., Schuettengruber, B., Cavalli, G. (2025). Determining the functional relationship between epigenetic and physical chromatin domains in Drosophila. Genome Biol, 26(1):116 PubMed ID: 40340859
Summary: The tight correlation between topologically associating domains (TADs) and epigenetic domains in Drosophila suggests that the epigenome contributes to define TADs. However, it is still unknown whether histone modifications are essential for TAD formation and structure. By either deleting or shifting key regulatory elements needed to establish the epigenetic signature of Polycomb TADs, this study showed that the epigenome is not a major driving force for the establishment of TADs. On the other hand, physical domains have an important impact on the formation of epigenetic domains, as they can restrict the spreading of repressive histone marks and looping between cis-regulatory elements. | Melnikova, L. S., Balagurov, K. I., Georgiev, P. G., Golovnin, A. K. (2025). Identification of a Highly Conserved Region Critical for the Functionality of the Cp190 Protein in Drosophila melanogaster. Dokl Biochem Biophys, 521(1):178-182 PubMed ID: 40216711
Summary: The CP190 protein binds to both housekeeping gene promoters and insulator/boundary elements and plays a critical role in their activity. The aim of this work was to study the effect of deletions in highly conserved regions of the CP190 protein on its functionality. It was shown that deletion of the sequence from 664 to 700 aa leads to a lethal phenotype. Thus, a new region was identified in CP190 that plays an important role in the interaction of the CP190 protein with as yet unidentified partner proteins, stabilization of protein complexes formed by CP190, and their recruitment to chromatin. |
Monday February 23rd -Disease Models |
| Liang, Z., Murugappan, S. K., Li, Y., Lai, M. N., Qi, Y., Wang, Y., Chan, H. Y. E., Lee, M. M., Chan, M. K. (2025). Gene delivery of SUMO1-derived peptide rescues neuronal degeneration and motor deficits in a mouse model of Parkinson's disease. Mol Ther, 33(7):3056-3072 PubMed ID: 40189878
Summary: Developing α-synuclein aggregation inhibitors is challenging because its aggregation process involves several microscopic steps and heterogeneous intermediates. Previous work identified a SUMO1-derived peptide, SUMO1(15-55), that exhibits tight binding to monomeric α-synuclein via SUMO-SUMO-interacting motif (SIM) interactions, and effectively blocks the initiation of aggregation and formation of toxic aggregates in vitro. In cellular and Drosophila models, SUMO1(15-55) was efficacious in protecting neuronal cells from α-synuclein-induced neurotoxicity and neuronal degeneration. Given the demonstrated ability of SUMO1(15-55) to sequester α-synuclein monomers thereby blocking oligomer formation, this study sought to evaluate whether it could be equally effective against the aggregation-prone familial mutant α-synuclein-A53T. SUMO1(15-55) is shown to selectively bind to monomeric α-synuclein-A53T, inhibits primary nucleation, and prevents the formation of structured protofibrils in vitro, thereby protecting neuronal cells from protofibril-induced cell death. Larval feeding of a designed His(10)-SUMO1(15-55) that exhibits enhanced sub-stoichiometric suppression of α-synuclein-A53T aggregation in vitro can ameliorate Parkinson's disease (PD)-related symptoms in α-synuclein-A53T transgenic Drosophila models, while its rAAV-mediated gene delivery can relieve the PD-related histological and behavioral deficiencies in an rAAV-α-synuclein-A53T mouse PD model. Thesee findings suggest that gene delivery of His(10)-SUMO1(15-55) may serve as a clinical therapy for a spectrum of α-synuclein-aggregation associated synucleinopathies. | Krzystek, T. J., Rathnayake, R., Zeng, J., Huang, J., Iacobucci, G., Yu, M. C., Gunawardena, S. (2025).. Opposing roles for GSK3β and ERK1-dependent phosphorylation of huntingtin during neuronal dysfunction and cell death in Huntington's disease. Cell Death Dis, 16(1):328 PubMed ID: 40263294
Summary: Huntington's disease (HD)Huntingtin (HTT) gene leading to axonal degeneration and significant neuronal death. Despite evidence for a scaffolding role for HTT in membrane-related processes such as endocytosis, vesicle transport, and vesicle fusion, it remains unclear how polyQ-expansion alters membrane binding during these processes. Using quantitative Mass Spectrometry-based proteomics on HTT-containing light vesicle membranes isolated from healthy and HD iPSC-derived neurons, significant changes were found in the proteome and kinome of signal transduction, neuronal translation, trafficking, and axon guidance-related processes. Through a combination of in vitro kinase assays, Drosophila genetics, and pharmacological inhibitors, GSK3β and ERK1 were identified to phosphorylate HTT and that these events play distinct and opposing roles during HD with inhibition of GSK3β decreasing polyQ-mediated axonal transport defects and neuronal cell death, while inhibition of ERK enhancing these phenotypes. Together, this work proposes two novel pathways in which GSK3β phosphorylation events exacerbate and ERK phosphorylation events mitigate HD-dependent neuronal dysfunction highlighting a highly druggable pathway for targeted therapeutics using already available small molecules. |
| Cao, Z., Zhang, C., Liu, L., Lei, H., Zhang, H., He, Y., Li, X., Xiang, Q., Wang, Y. F., Zhang, L., Chen, G. (2025). Microbiota-derived indole acetic acid extends lifespan through the AhR-Sirt2 pathway in Drosophila. mSystems, 10(5):e0166524 PubMed ID: 40197001
Summary: Disruption of aryl hydrocarbon receptor (AhR) signaling and aberrant tryptophan metabolism have been shown to be highly associated with aging and age-related disorders. However, the underlying molecular mechanisms by which the AhR-mediated signaling pathway contributes to the aging process remain largely unknown. This study finds that aged Drosophila exhibits markedly reduced tryptophan metabolism leading to impaired AhR ligands, especially indole acetic acid (IAA), compared with their young controls. Supplementation with IAA, produced from Lactobacillus spp., dose-dependently extends the lifespan of Drosophila and improves healthy aging with resistance to starvation and oxidative stress. Mechanistically, activation of AhR by IAA markedly enhances Sirt2 activity by binding to its promoter, thereby inhibiting downstream TOR signaling and related fatty acid and amino acid metabolism. Both Ahr and Sirt2 mutant flies with IAA supplementation display a negligible lifespan extension, suggesting that AhR-mediated Sirt2 signaling contributes to lifespan extension in flies upon IAA supplementation. From the perspective of host metabolism, IAA supplementation significantly increases unsaturated fatty acids (UFAs) in aged flies, which are regarded to be beneficial for healthy status. These findings provide new insights into the physiological functions of AhR involved in the aging process by mediating Sirt2 signaling. | Buhl, E., Garg, S., Monaghan, M., Preston, A., Likeman, M., Dare, J., Evans, J., Taylor, L. S., Berry, I., Urankar, K., Spry, P. G. D., Williams, C., Taylor, R. W., Alston, C. L., Hodge, J. J. L., Majumdar, A. (2025). Infantile Cerebellar-Retinal Degeneration Associated With Novel ACO2 Variants: Clinical Features and Insights From a Drosophila Model. Clin Genet, PubMed ID: 40210596
Summary: Infantile Cerebellar-Retinal Degeneration (ICRD) is an autosomal recessive neuro-disability associated with hypotonia, seizures, optic atrophy, and retinal degeneration. Recessive variants of the mitochondrial aconitase gene (ACO2) are a known cause of ICRD. This study presents a paediatric male patient with ICRD, where whole genome sequencing of the family trio revealed segregating heterozygous variants of unknown significance in ACO2. At 4 months, he displayed generalised hypotonia, and by 6 years, visual electrophysiology indicated bilateral optic atrophy. Magnetic Resonance Imaging (MRI) at age seven confirmed optic nerve and cerebellar atrophy, and together with symptoms of developmental delay, align with ICRD. A Drosophila animal model was established to explore the impact of ACO2 loss- and gain-of-function. Manipulating the fly ortholog, mAcon1, through pan-neuronal knock-down or over-expression negatively affected longevity, locomotion, activity, whilst disrupting sleep and circadian rhythms. Mis-expression of mAcon1 in the eye led to impaired visual synaptic transmission and neurodegeneration. These experiments mirrored certain aspects of the human disease, providing a foundation for understanding its biological processes and pathogenic mechanisms, and offering insights into potential targets to screen for future treatments or preventive measures for ACO2-related ICRD. |
| He, G., Sun, J., Gu, Y., Zheng, Y., Wang, L., Sun, Y. (2025). Network analysis and in vivo experiments reveal the therapeutic mechanisms of total ginsenosides in a Drosophila model of ulcerative colitis. Front Pharmacol, 16:1556579 PubMed ID: 40201696
Summary: Gut homeostasis is critical for human health, ulcerative colitis (UC) can disrupt gut homeostasis and cause disease. Panax ginseng C.A. Meyer is a widely used traditional herbal medicine known for its anti-inflammatory, antioxidant, and immunomodulatory effects. However, the protective mechanisms of total ginsenosides (TG) in treating UC remain unclear. In this study, we employed Drosophila melanogaster as a model organism to investigate the protective effects of TG on dextran sulfate sodium (DSS)-induced intestinal injury. Our data showed that TG significantly improved survival rates in female flies, restored intestinal length, maintained intestinal barrier integrity, and alleviated oxidative stress. Additionally, TG may protect against intestinal damage by activating the PI3K/Akt signaling pathway and inhibiting the JAK/STAT signaling pathway. These findings suggest that TG alleviates UC symptoms through multi-target regulation, highlighting its potential for developing novel therapeutic strategies for UC. | Ham, S. J., Yoon, E., Lee, D. H., Kim, S., Yoo, H., Chung, J. (2025). Reciprocal rescue of Wolfram syndrome by two causative genes.EMBO Rep, 26(9):2459-2482 PubMed ID: 40181095
Summary: Wolfram syndrome (WS) is marked by juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing loss. The causative genes, WFS1 and CISD2, correspond to WS types 1 and 2, respectively. This study establishes their mutual indispensability for inositol 1,4,5-triphosphate receptor (IP(3)R) activity, demonstrating their ability to restore reduced IP(3)R activity in WFS1- or CISD2-deficient mammalian cells. Additionally, Drosophila WS models lacking dWFS1 or dCISDM exhibit diabetes-like phenotypes analogous to WS patients, and overexpression of dWFS1 and dCISD in the flies alleviates their phenotypes. A peptide containing the CDGSH domain of CISD2, critical for its interaction with IP(3)R was engineered. Overexpression of the CISD2 peptide or treatment with its cell-penetrating peptide (CPP)-conjugated form restores calcium homeostasis in WFS1- or CISD2-deficient cells, and overexpressing the homologous dCISD peptide suppresses diabetes-like phenotypes in WS model flies. These findings underscore the intricate involvements of WFS1 and CISD2 in ER calcium regulation and provide potential therapeutic prospects for WS-related diabetes. |
Thursday February 20th - Larval and adult neural development, structure and function |
| Gattuso, H. C., van Hassel, K. A., Freed, J. D., Nunez, K. M., de la Rea, B., May, C. E., Ermentrout, B., Victor, J. D., Nagel, K. I. (2025). Inhibitory control explains locomotor statistics in walking Drosophila. Proc Natl Acad Sci U S A, 122(16):e2407626122 PubMed ID: 40244663
Summary: In order to forage for food, many animals regulate not only specific limb movements but the statistics of locomotor behavior, switching between long-range dispersal and local search depending on resource availability. How premotor circuits regulate locomotor statistics is not clear. This study analyzed and modeled locomotor statistics and their modulation by attractive food odor in walking Drosophila. Food odor evokes three motor regimes in flies: baseline walking, upwind running during odor, and search behavior following odor loss. During search, this study found that flies adopt higher angular velocities and slower ground speeds and turn for longer periods in the same direction. Flies were further found to adopt periods of different mean ground speed and that these state changes influence the length of odor-evoked runs. We next developed a simple model of neural locomotor control that suggests that contralateral inhibition plays a key role in regulating the statistical features of locomotion. As the fly connectome predicts decussating inhibitory neurons in the (for information on premotor lateral accessory lobe neurons, go to Google AI and query premotor lateral accessory lobe neurons Drosophila) premotor lateral accessory lobe (LAL), genetic access was gained to a subset of these neurons, and their effects on behavior were tested. One population was identified whose activation induces all three signature of local search and that regulates angular velocity at odor offset. A second population, including a single LAL neuron pair, bidirectionally regulates ground speed. Together, this work develops a biologically plausible computational architecture that captures the statistical features of fly locomotion across behavioral states and identifies neural substrates of these computations. | Lee, W. P., Chiang, M. H., Chao, Y. P., Wang, Y. F., Chen, Y. L., Lin, Y. C., Jenq, S. Y., Lu, J. W., Fu, T. F., Liang, J. Y., Yang, K. C., Chang, L. Y., Wu, T., Wu, C. L. (2025). Dynamics of two distinct memory interactions during water seeking in Drosophila. Proc Natl Acad Sci U S A, 122(16):e2422028122 PubMed ID: 40244670
Summary: Forming and forgetting memories shape self-awareness and help facing future challenges. Therefore, understanding how memories are formed and how different memories interact in the brain is important. Previous studies have shown that thirsty flies sense humidity through ionotropic receptors, which help them locate water sources. This study showed that thirsty flies can be trained to associate specific odors with humidity to form a humidity memory that lasts for 30 min after association. Humidity memory formation requires the interactions during water seeking in Drosophila. Proc Natl Acad Sci U S A, 122(16):e2422028122 PubMed ID: Ir93a and es the interactions during water seeking in Drosophila. Proc Natl Acad Sci U S A, 122(16):e2422028122 PubMed ID: Ir40a ionotropic receptors, which are essential for environmental humidity sensing. Water memory takes precedence, leading to the forgetting of humidity memory by activating a small subset of dopaminergic neurons called protocerebral anterior medial (PAM)-&gamma4 (for information on NEURON neurons, go to Google AI and query protocerebral anterior medial (PAM)-&gamma4), that project to the restricted region of the mushroom body (MB) γ lobes. Adult-stage-specific silencing of Dop2R dopaminergic receptors in MB γ neurons prolongs humidity memory &gamma4; neural activity after odor/humidity association, suggesting its role in forgetting the humidity memory. These results suggest that overlapping neural circuits are responsible for the acquisition of water memory and forgetting humidity memory in thirsty flies. |
| Francis, J., Gibeily, C. R., Smith, W. V., Petropoulos, I. S., Anderson, M., Heitler, W. J., Prinz, A. A., Pulver, S. R. (2025). Inhibitory circuit motifs in Drosophila larvae generate motor program diversity and variability. PLoS Biol, 23(4):e3003094 PubMed ID: 40258087
Summary: How do neural networks generate and regulate diversity and variability in motor outputs with finite cellular components? This study examined this problem by exploring the role that inhibitory neuron motifs play in generating mixtures of motor programs in the segmentally organised Drosophila larval locomotor system. A computational model was developed that is constrained by experimental calcium imaging data. The model comprises single-compartment cells with a single voltage-gated calcium current, which are interconnected by graded excitatory and inhibitory synapses. Local excitatory and inhibitory neurons form conditional oscillators in each hemisegment. Surrounding architecture reflects key aspects of inter- and intrasegmental connectivity motifs identified in the literature. The model generates metachronal waves of activity that recapitulate key features of fictive forwards and backwards locomotion, as well as bilaterally asymmetric activity in anterior regions that represents fictive head sweeps. The statistics of inputs to competing command-like motifs, coupled with inhibitory motifs that detect activity across multiple segments generate network states that promote diversity in motor outputs, while at the same time preventing maladaptive overlap in motor programs. Overall, the model generates testable predictions for connectomics and physiological studies while providing a platform for uncovering how inhibitory circuit motifs underpin generation of diversity and variability in motor systems (Francis, 2025). | Martinez-Cordera, M., Sakai, T., Saitoe, M., Ueno, K. (2025). Comparative experience shapes sucrose preference through memory in Drosophila. Mol Brain, 18(1):32 PubMed ID: 40211246
Summary: \Selection of appropriate food is an ability that allows animals to make optimal foraging choices. However, the neural mechanisms that control this food selection remain unclear. The purpose of this study was to investigate the connection between memory and the feeding behavior of Drosophila melanogaster when two sucrose solutions with different concentrations are available. We placed flies into plates with 150 mM and 100 mM sucrose solutions and measured the preference for the 150 mM one. Flies preferred the 150 mM solution over the 100 mM when all 60 wells of the plate were filled with both solutions; this preference decreased when there were only 8 wells with food. Remarkably, prior exposure to a plate with all 60 wells filled with both solutions enhanced the preference for the 150 mM, even when there were only 8 wells with food. The memory-related gene rut and the dopamine D1 receptor on the mushroom body were required to enhance the preference after the prior exposure. These findings show that memory acquired through experiencing both solutions is stored in the mushroom body optimizing the food selection process (Martinez-Cordera. 2025. |
| Lu, W., Lee, B. S., Deng, H. X. Y., Lakonishok, M., Martin-Blanco, E., Gelfand, V. I. (2025). 'Mitotic' kinesin-5 is a dynamic brake for axonal growth in Drosophila. Development, 152(9) PubMed ID: 40223510
Summary: During neuronal development, microtubule reorganization shapes axons and dendrites, establishing the framework for efficient nervous system wiring. Previous work has demonstrated the role of kinesin-1 in driving microtubule sliding, which powers early axon outgrowth and regeneration in Drosophila melanogaster. This study reveals a crucial new role for kinesin-5, a mitotic motor, in modulating postmitotic neuron development. The Drosophila kinesin-5, Klp61F, is expressed in larval brain neurons, with high levels in ventral nerve cord (VNC) neurons. Knockdown of Klp61F in neurons leads to severe adult locomotion defects and lethality, primarily due to defects in VNC motor neurons. Klp61F depletion results in excessive microtubule penetration into the axon growth cone, causing significant axon growth defects in culture and in vivo. These defects are rescued by a chimeric human-Drosophila kinesin-5 motor, indicating a conserved role for kinesin-5 in neuronal development. Altogether, it is proposed that kinesin-5 acts as a brake on kinesin-1-driven microtubule sliding, ensuring proper axon pathfinding in growing neurons (Lu, 2025). | Flores-Valle, A., Vishniakou, I., Seelig, J. D. (2025). Dynamics of glia and neurons regulate homeostatic rest, sleep and feeding behavior in Drosophila. Nat Neurosci, 28(6):1226-1240 PubMed ID: 40259071
Summary: Homeostatic processes, including sleep, are critical for brain function. This study identified astrocyte-like glia (or astrocytes, AL) and ensheathing glia (EG), the two major classes of glia that arborize inside the brain, as brain-wide, locally acting homeostats for the short, naturally occurring rest and sleep bouts of Drosophila, and show that a subset of neurons in the fan-shaped body encodes feeding homeostasis.The metabolic gas carbon dioxide, changes in pH and behavioral activity all induce long-lasting calcium responses in EG and AL, and that calcium levels in both glia types show circadian modulation. The homeostatic dynamics of these glia can be modeled based on behavior. Additionally, local optogenetic activation of AL or EG is sufficient to induce rest. Together, these results suggest that glial calcium levels are homeostatic controllers of metabolic activity, thus establishing a link between metabolism, rest and sleep (Flores-Valle, 2025). |
Wednesday February 18th - Disease Models |
| Gonzalez-Gutierrez, A., Gaete, J., Esparza, A., Ibacache, A., Contreras, E. G., Sierralta, J. (2025). Starvation Induces Upregulation of Monocarboxylate Transport in Glial Cells at the Drosophila Blood-Brain Barrier. Glia, 73(8):1608-1626 PubMed ID: 40241296
Summary: Living organisms can sense and adapt to constant changes in food availability. Maintaining a homeostatic supply of energy molecules is crucial for animal survival and normal organ functioning, particularly the brain, due to its high-energy demands. However, the mechanisms underlying brain adaptive responses to food availability have not been completely established. The nervous system is separated from the rest of the body by a physical barrier called the blood-brain barrier (BBB). In addition to its structural role, the BBB regulates the transport of metabolites and nutrients into the nervous system. This regulation is achieved through adaptive mechanisms that control the transport of nutrients, including glucose and monocarboxylates such as lactate, pyruvate, and ketone bodies. In Drosophila melanogaster, carbohydrate transporters increase their expression in glial cells of the BBB in response to starvation. However, changes in the expression or activity of Drosophila monocarboxylate transporters (dMCTs) at the BBB have not yet been reported. This study showed that neuronal ATP levels remain unaffected despite reduced energy-related metabolites in the hemolymph of Drosophila larvae during starvation. Simultaneously, the transport of lactate and beta-hydroxybutyrate increases in the glial cells of the BBB. Using genetically encoded sensors, this study identified Yarqay as a proton-coupled monocarboxylate transporter whose expression is upregulated in the subperineurial glia of the BBB during starvation. These findings reveal a novel component of the adaptive response of the brain to starvation: the increase in the transport of monocarboxylates across the BBB, mediated by Yarqay, a novel dMCT enriched in the BBB. | Zhang, X., Su, K. J., Banerjee, B., Eres, I., Hsu, Y. H., Crandall, C. J., Donaka, R., Han, Z., Jackson, R. D., Liu, H., Luo, Z., Mitchell, B. D., Qiu, C., Tian, Q., Shen, H., Tsai, M. J., Wiggins, K. L., Xu, H., Yau, M., Zhao, L. J., Zhang, X., Montasser, M. E., Kiel, D. P., Deng, H. W., Liu, C. T., Karasik, D. (2025). Multi-ancestry whole genome sequencing analysis of lean body mass. Genome Biol, 26(1):106 PubMed ID: 40296127
Summary: Lean body mass is a crucial physiological component of body composition. Although lean body mass has a high heritability, studies evaluating the genetic determinants of lean mass (LM) have to date been limited largely to genome-wide association studies (GWAS) and common variants. Using whole genome sequencing (WGS)-based studies, this study aimed to discover novel genetic variants associated with LM in population-based cohorts with multiple ancestries. The largest WGS-based meta-analysis of lean body mass to date is descrubed, encompassing 10,729 WGS samples from six TOPMed cohorts and the Louisiana Osteoporosis Study (LOS) cohort, measured with dual-energy X-ray absorptiometry. We identify seven genome-wide loci significantly associated with LM not reported by previous GWAS. These associations were partially reolicated in UK Biobank samples. In rare variant analysis, one novel protein-coding gene, DMAC1, was discovered associated with both whole-body LM and appendicular LM in females, and a long non-coding RNA gene linked to appendicular LM in males. Both genes exhibit notably high expression levels in skeletal muscle tissue. We investigate the functional roles of two novel lean-mass-related genes, EMP2 and SSUH2, in animal models. EMP2 deficiency in Drosophila leads to significantly reduced mobility without altering muscle tissue or body fat morphology, whereas an SSUH2 gene mutation in zebrafish stimulates muscle fiber growth. CONCLUSIONS: Our comprehensive analysis, encompassing a large-scale WGS meta-analysis and functional investigations, reveals novel genomic loci and genes associated with lean mass traits, shedding new insights into pathways influencing muscle metabolism and muscle mass regulation. |
| Guo, F. R., Wang, S. C., Liu, Y., Wang, S., Huang, J. M., Sun, H., He, L. F., Xie, Y., Qiao, S. T., Yang, F. X., Bass, C., Gao, C. F., Wu, S. F. (2025). CYP321F3 mediates metabolic resistance to methoxyfenozide in rice stem borer, Chilo suppressalis. Pestic Biochem Physiol, 210:106383 PubMed ID: 40262888
Summary: The development of insecticide resistance in insect populations is a major challenge to sustainable agriculture and food security worldwide. Methoxyfenozide, an insect growth regulator that acts as an agonist of 20-hydroxyecdysone (20E), has severely declined in its efficacy against the rice stem borer (Chilo suppressalis), a notorious pest of rice crops in East and Southeast Asia. To date, however, the genes involved in methoxyfenozide resistance in target pests remain unclear. A long-term (seven years from 2017 to 2023) and large geographical scale (8 provinces and 45 cities in China) resistance monitoring program were conducted for methoxyfenozide in C. suppressalis. Resistance was seen to arise rapidly in this species, with >100-fold resistance being detected in nearly all the field populations after 2018. Piperonyl butoxide (PBO), an inhibitor of cytochrome P450 enzymes (P450s), significantly increased the sensitivity of resistant strains of C. suppressalis to methoxyfenozide, implicating P450s in resistance. Six P450 genes: CYP321F3, CYP6CV5, CYP9A68, CYP6AB45, CYP324A12 and CYP6SN2 were identified as highly expressed in resistant C. suppressalis by transcriptome profiling. Of these, ectopic expression of CYP321F3 in Drosophila melanogaster resulted in a 7.0-fold increase in resistance to methoxyfenozide demonstrating its causal role in resistance. Collectively, these findings provide insight into the mechanisms mediating resistance to insect growth regulators and will inform the development of future pest and resistance management strategies. | Lei, C., Chen, Z., Hao, Y., Huang, W., Chu, T., Xiao, K., Zhang, C., Zhou, W., Li, C., Chen, X. (2025). Quantitative and site-specific chemoproteomic profiling of O-GlcNAcylation in Drosophila. Bioorg Med Chem, 124:118191 PubMed ID: 40245499
Summary: Protein O-GlcNAcylation plays a crucial role in Drosophila melanogaster development. Dysregulation of O-GlcNAc transferase (sxc/Ogt) and GlcNAcase (Oga) disrupts early embryogenesis and locomotor behavior. It is therefore of great interest to identify and quantitatively analyze O-GlcNAcylation sites in Drosophila. This study performed quantitative and site-specific profiling of O-GlcNAcylation in Drosophila by employing a chemoenzymatic labeling strategy. A total of 2196 unambiguous O-GlcNAcylation sites and 1308 O-GlcNAcylated proteins are identified. Quantitative analysis of O-GlcNAcylation in the head of Drosophila with sxc/Ogt knockdown in GABAergic neurons reveals a reduction in O-GlcNAcylation of several proteins involved in muscle development, consistent with the phenotypic defects observed in sxc/Ogt. RNAi Drosophila. Furthermore, quantitative analysis of O-GlcNAcylation under a high-sugar diet reveals altered O-GlcNAcylation of several proteins associated with obesity and neurological diseases, such as Hex-A and Ankyrin 2. This study not only establishes an effective method for large-scale identification of O-GlcNAcylation sites, but also provides a valuable resource for studying O-GlcNAc biology in Drosophila. |
| Abou Daya, F., Mandigo, T., Ober, L., Patel, D., Maher, M., Math, S., Tchio, C., Walker, J. A., Saxena, R., Melkani, G. C. (2025). Identifying links between cardiovascular disease and insomnia by modeling genes from a pleiotropic locus. Dis Model Mech, 18(5) PubMed ID: 40176577
Summary: Insomnia symptoms double the risk of cardiovascular disease (CVD), yet shared genetic pathways remain unclear. Genome-wide association studies identified a genetic locus (near ATP5G1, UBE2Z, SNF8, IGF2BP1 and GIP) linked to insomnia and CVD. Drosophila models were used to perform tissue-specific RNA interference knockdowns of four conserved orthologs (ATPsynC, lsn, Bruce and Imp) in neurons and the heart. Neuronal-specific knockdown of ATPsynC, Imp and lsn impaired sleep quantity and quality. In contrast, cardiac knockdown of ATPsynC and lsn reduced cardiac function and lifespan, with lsn knockdown also causing cardiac dilation and myofibrillar disorganization. Cross-tissue effects were evident: neuronal Imp knockdown compromised cardiac function, whereas cardiac ATPsynC and lsn knockdown increased sleep fragmentation and inflammation (marked by Upd3 elevation in the heart or head). Overexpression of Upd3 in neurons impaired cardiac function, and its overexpression in the heart disrupted sleep. These findings reveal conserved genes mediating tissue-specific and cross-tissue interactions between sleep and cardiac function, providing novel insights into the genetic mechanisms linking insomnia and CVD through inflammation. | Geronazzo, J., Heimerl, A., Lindell, L., McCrimmon, S., Stormer, C., Horvai, B., Johnson, I. P., Peterson, T. M., Zuckerman, J., Scott, A. I., Course, M. M. (2025). Characterizing fatty acid oxidation genes in Drosophila. G3 (Bethesda), PubMed ID: 40519079
Summary: This study leveraged the power and tractability of Drosophila genetics to better understand the molecular mechanisms underlying a group of rare genetic diseases known as fatty acid oxidation disorders. CRISPR-Cas9 was used to generate mutations in six putative fatty acid oxidation genes in Drosophila, then analyze the phenotypes and acylcarnitine profiles of these flies. While Arc42 and CG4860 are both predicted orthologs of human ACADS, only Arc42 loss of function mirrors the acylcarnitine profile of ACADS loss of function. Acylcarnitine profiles also support a previous identification of Mcad as the likely ACADM ortholog, and reveal the deleterious effects of a single codon deletion in Mtp&alpha: (the predicted human HADHA ortholog). Finally, it was observed that loss of function in Etf-QO and in CG7834-predicted orthologs of human ETFDH and ETFB, respectively-is homozygous lethal in flies. Producing animal models like these will enable new approaches to studying fatty acid oxidation disease progression, symptomatic variability, and therapeutic intervention. |
Tuesday February 17th - Disease Models |
| He, L., Zhang, Y., Li, J., Chen, D., Yue, S., Liu, Y., Guo, Y., Wang, Y., Xiu, M., He, J. (2025). Dunhuang Dabupi Decoction and its active components alleviate ulcerative colitis by activating glutathione metabolism and inhibiting JAK-STAT pathway in Drosophila and mice. J Ethnopharmacol, 346:119717 PubMed ID: 40164365
Summary: Dabupi Decoction (DBPD) originates from the ancient Dunhuang medical literature "Fu Xing Jue Visceral to Drug law legend" for more than 1000 years, which has been extensively employed to treat various diseases related to the spleen and stomach. However, limited studies focus on the mechanism of DBPD against ulcerative colitis (UC). The beneficial effect and mechanism of DBPD against UC were detected by adopting both Drosophila melanogaster and C57BL/6J mouse models. The protective effect of DBPD against DSS-induced intestinal damage in flies was investigated In mice, Liquid chromatography-mass spectrometry (LC-MS) and phenotype experiments in UC flies were utilized to identify the bioactive components of DBPD against UC. Oral administration of DBPD remarkably alleviated DSS-induced body damage in flies by improving survival rate, locomotion, and excretion. It also remarkably rescued intestinal morphological damage, repaired acid-base homeostatic imbalance, inhibited intestinal epithelial cells (IECs) death and excessive proliferation of intestinal stem cells (ISCs), and improved ultrastructural damage of IECs in flies treated with DSS. Consistently, DBPD attenuated colitis symptoms, alleviated intestinal histopathological damage, and restored the expression of inflammatory factors in DSS-induced UC mice. As suggested by an integration of transcriptome data with molecular biology experiments, DBPD not only dramatically alleviated oxidative damage by activating the glutathione metabolic pathway, but also lowered inflammatory reaction by inhibiting the JAK-STAT pathway. Additionally, four compounds of DBPD, rhein acid, isoquercitrin, curcumin, and zeaxanthin were identified to alleviate the DSS-induced intestinal injury. CONCLUSION: DBPD demonstrate immense potential for intestinal injury predominantly by activating the glutathione metabolic pathway to alleviate oxidative damage, and inhibiting the JAK-STAT pathway to mitigate inflammatory response. Rhein acid, isoquercitrin, curcumin, and zeaxanthin were the bioactive compounds of DBPD against UC. | Heckmann, M., Sadova, N., Sandner, G., Neuhauser, C., Blank-Landeshammer, B., Schwarzinger, B., Konig, A., Liang, M., Spitzer, M., Weghuber, J., Stadlbauer, V. (2025). Herbal extract fermented with inherent microbiota improves intestinal health by exerting antioxidant and anti-inflammatory effects in vitro and in vivo. J Anim Sci Biotechnol, 16(1):52 PubMed ID: 40188119
Summary: Maintaining intestinal health is crucial for the overall well-being and productivity of livestock, as it impacts nutrient absorption, immune function, and disease resistance. Oxidative stress and inflammation are key threats to intestinal integrity. This study explored the antioxidant, anti-inflammatory, and barrier-strengthening properties of a fermented plant macerate (FPM) derived from 45 local herbs, using a specifically developed fermentation process utilizing the plants' inherent microbiota to enhance bioactivity and sustainability. In vitro experiments with IPEC-J2 cells showed that FPM significantly reduced intracellular reactive oxygen species (ROS) levels, improved barrier integrity, and enhanced cell migration under stress. Similar antioxidant effects were observed in THP-1 macrophages, where FPM reduced ROS production and modulated inflammatory responses by decreasing pro-inflammatory cytokines [tumor necrosis factor alpha (TNF-α), monokine induced by gamma interferon (MIG), interferon-inducible T cell alpha chemoattractant (I-TAC), macrophage inflammatory proteins (MIP)-1α and -1β] and increasing anti-inflammatory interleukin (IL)-10 levels. Mechanistic studies with HEK-Blue reporter cell lines revealed that FPM inhibited nuclear factor kappa B (NF-kappaB) activation via a FBgn0032095">toll-like receptor (TLR)4-independent pathway. In vivo, FPM significantly reduced ROS levels in Drosophila melanogaster and improved activity and LT(50) values in Caenorhabditis elegans under oxidative stress, although it did not affect intestinal barrier integrity in these models. The findings indicate that FPM shows promising application as a functional feed supplement for improving intestinal health in livestock by mitigating oxidative stress and inflammation. Further studies, including livestock feeding trials, are recommended to validate these results. |
| Justice, J. L., Greco, T. M., Hutton, J. E., Reed, T. J., Mair, M. L., Botas, J., Cristea, I. M. (2025). Multi-epitope immunocapture of huntingtin reveals striatum-selective molecular signatures. Mol Syst Biol, 21(5):492-522 PubMed ID: 40169779
Summary: Huntington's disease (HD) is a debilitating neurodegenerative disorder affecting an individual's cognitive and motor abilities. HD is caused by a mutation in the huntingtin gene producing a toxic polyglutamine-expanded protein (mHTT) and leading to degeneration in the striatum and cortex. Yet, the molecular signatures that underlie tissue-specific vulnerabilities remain unclear. This aspect was investigated by leveraging multi-epitope protein interaction assays, subcellular fractionation, thermal proteome profiling, and genetic modifier assays. The use of human cell, mouse, and fly models afforded capture of distinct subcellular pools of epitope-enriched and tissue-dependent interactions linked to dysregulated cellular pathways and disease relevance. An HTT association was established with nearly all subunits of the transcriptional regulatory Mediator complex (20/26), with preferential enrichment of MED15 in the tail domain. Using HD and KO models, this study found HTT modulates the subcellular localization and assembly of the Mediator. striatal enriched and functional interactions were demonstrated with regulators of calcium homeostasis and chromatin remodeling, whose disease relevance was supported by HD fly genetic modifiers assays. Altogether, we offer insights into tissue- and localization-dependent (m)HTT functions and pathobiology. | Huang, Y., Xiang, Z., Xiang, Y., Pan, H., He, M., Guo, Z., Kanca, O., Liu, C., Zhang, Z., Zhan, H., Wang, Y., Bai, Q. R., Bellen, H. J., Wang, H., Bian, S., Mao, X. (2025). Biallelic MED16 variants disrupt neural development and lead to an intellectual disability syndrome. J Genet Genomics, PubMed ID: 40254158
Summary: Mediator Complex Subunit 16 (MED16, MIM: 604062) is a member of the Mediator complex, which controls many aspects of transcriptional activity in all eukaryotes. This study reports two individuals from a non-consanguineous family with biallelic variants in MED16 identified by exome sequencing. The affected individuals present with global developmental delay, intellectual disability, and dysmorphisms. To assess the pathogenicity of the variants, functional studies are performed in Drosophila and patient-derived cells. The fly ortholog med16 is expressed in neurons and some glia of the developing central nervous system (CNS). Loss of med16 leads to a reduction in eclosion and lifespan, as well as impaired synaptic transmission. In neurons differentiated from the patient-derived induced pluripotent stem cells (iPSCs), the neurite outgrowth is impaired and rescued by expression of exogenous MED16. The patient-associated variants behave as loss-of-function (LoF) alleles in flies and iPSCs. Additionally, the transcription of genes related to neuronal maturation and function is preferentially altered in patient cells relative to differentiated H9 controls. In summary, these findings support that MED16 is important for appropriate development and function, and that biallelic MED16 variants cause a neurodevelopmental disease. |
| Kirio, K., Patop, I. L., Anduaga, A. M., Harris, J., Pamudurti, N., Su, T. N., Martel, C., Kadener, S. (2025). Circular RNAs exhibit exceptional stability in the aging brain and serve as reliable age and experience indicators. ell Rep, 44(4):115485 PubMed ID: 40184256
Summary: Circular RNAs (circRNAs) increase in the brain with age across various animal systems. To elucidate the reasons behind this phenomenon, this study profile circRNAs from fly heads at six time points throughout their lifespan. The results reveal a linear increase in circRNA levels with age, independent of changes in mRNA levels, overall transcription, intron retention, or host gene splicing, demonstrating that the age-related accumulation is due to high stability rather than increased biogenesis. This remarkable stability suggests that circRNAs can serve as markers of environmental experience. Indeed, flies exposed to a 10-day regimen at 29°deg;C exhibit higher levels of specific circRNAs even 6 weeks after returning to standard conditions, indicating that circRNAs can reveal past environmental stimuli. Moreover, half-life measurements show circRNA stability exceeding 20 days, with some displaying virtually no degradation. These findings underscore the remarkable stability of circRNAs in vivo and their potential as markers for stress and life experiences. | Keesey, I. W., Doll, G., Chakraborty, S. D., Baschwitz, A., Lemoine, M., Kaltenpoth, M., Svatos, A., Sachse, S., Knaden, M., Hansson, B. S. (2025). Neuroecology of alcohol risk and reward: Methanol boosts pheromones and courtship success in Drosophila melanogaster. Sci Adv, 11(14):eadi9683 PubMed ID: 40173238
Summary: Attraction of Drosophila melanogaster toward by-products of alcoholic fermentation, especially ethanol, has been extensively studied. Previous research has provided several interpretations of this attraction, including potential drug abuse, or a self-medicating coping strategy after mate rejection. We posit that the ecologically adaptive value of alcohol attraction has not been fully explored. Here, the authors assert a simple yet vital biological rationale for this alcohol preference. Flies display attraction to fruits rich in alcohol, specifically ethanol and methanol, where contact results in a rapid amplification. Olfactory sensory neurons that detect these alcohols, where roles were revealed in both attraction and aversion, and show that valence is balanced around alcohol concentration. Moreover,methanol can be deadly, and adult flies must therefore accurately weigh the trade-off between benefits and costs for exposure within their naturally fermented and alcohol-rich environments. |
Wednesday January 28th - Behavior |
| Huang, Y. C., Costa, C. A. M., Ruiz, N. V., Wang, X., Jevitt, A., Breneman, C. M., Han, C., Deng, W. M. (2025). Polyploidy promotes transformation of epithelial cells into non-professional phagocytes. bioRxiv, PubMed ID: 40196694
Summary: Removal of dead and damaged cells is critical for organismal health. Under stress conditions such as nutritional deprivation, infection, or temperature shift, the clearance of nonessential cells becomes a universal strategy to conserve energy and maintain tissue homeostasis. Typically, this task is performed by professional phagocytes such as macrophages. However, non-professional phagocytes (NPPs) can also adopt a phagocytic fate under specific circumstances. Similar to professional phagocytes, NPPs undergo transitions from immature to mature states and activation, but the precise cellular and molecular mechanisms governing their maturation, induction and phagocytic execution remain largely unknown. A notable example of stress-induced phagocytosis is the removal of germline cells by follicle cell-derived NPPs during oogenesis in Drosophila. This study reports that the transformation of follicle cells into NPPs is dependent on Notch signaling activation during mid-oogenesis. Moreover, Notch overactivation is sufficient to trigger germline cell death and clearance (GDAC). It was further shown that polyploidy, driven by Notch signaling-induced endoreplication, is essential for the transformation of follicle cells into NPPs. Polyploidy facilitates the activation of JNK signaling, which is crucial for the phagocytic behavior of these cells. Additionally, polyploidy in epidermal cells, another type of NPPs, is shown to be important for their engulfment of dendrites during induced degeneration. Together, these findings suggest that polyploidy is a critical factor in the transformation of epithelial cells into NPPs, enabling their phagocytic functions, which are essential for maintaining cellular and organismal homeostasis during stress conditions. | Singh, J., Verma, D., Sarkar, B., Paul, M. S., Mutsuddi, M., Mukherjee, A. (2025). Notch and LIM-homeodomain protein Arrowhead regulate each other in a feedback mechanism to play a role in wing and neuronal development in Drosophila. Open Biol, 15(4):240247 PubMed ID: 40300650
Summary: The Notch pathway is an evolutionarily conserved signalling system that operates to influence an astonishing array of cell fate decisions in different developmental contexts. To identify novel effectors of Notch signalling, this study analysed the whole transcriptome of Drosophila wing and eye imaginal discs in which an activated form of Notch was overexpressed. A LIM-homeodomain protein, Arrowhead (Awh), was identified as a novel candidate that plays a crucial role in Notch-mediated developmental events. Awh alleles show strong genetic interaction with Notch pathway components. Awh loss-of-function upregulates Notch targets Cut and Wingless. Awh gain-of-function downregulates Notch targets by reducing the expression of the ligand Delta. Consequently, the expression of the Wingless effector molecule Armadillo and its downstream targets, Senseless and Vestigial, also gets downregulated. Awh overexpression leads to ectopic expression of engrailed, a segment polarity gene in the anterior region of wing disc, leading to patterning cdefects. Additionally, Notch gain-of-function-mediated neuronal defects get significantly rescued with Awh overexpression. Activated Notch inhibits Awh activity, suggesting a regulatory loop between Awh and Notch. Additionally, the defects caused by Awh gain-of-function were remarkably rescued by Chip, a LIM interaction domain containing transcriptional co-factor. The present study highlights the novel feedback regulation between Awh and Notch. |
| Fujinaga, D., Nolan, C., Yamanaka, N. (2025). Functional characterization of eicosanoid signaling in Drosophila development. PLoS Genet, 21(5):e1011705 PubMed ID: 40344083
Summary: 20-carbon fatty acid-derived eicosanoids are versatile signaling oxylipins in mammals. In particular, a group of eicosanoids termed prostanoids are involved in multiple physiological processes, such as reproduction and immune responses. Although some eicosanoids such as prostaglandin E2 (PGE2) have been detected in some insect species, molecular mechanisms of eicosanoid synthesis and signal transduction in insects have not been thoroughly investigated. Phylogenetic analysis indicated that, in clear contrast to the presence of numerous receptors for oxylipins and other lipid mediators in humans, the Drosophila genome only possesses a single ortholog of such receptors, which is homologous to human prostanoid receptors. This G protein-coupled receptor, named Prostaglandin Receptor or PGR, is activated by PGE2 and its isomer PGD2 in Drosophila S2 cells. PGR mutant flies die as pharate adults with insufficient tracheal development, which can be rescued by supplying high oxygen. Consistent with this, through a comprehensive mutagenesis approach, this study identified a Drosophila PGE synthase whose mutants show similar pharate adult lethality with hypoxia responses. Drosophila thus has a highly simplified eicosanoid signaling pathway as compared to humans, and it may provide an ideal model system for investigating evolutionarily conserved aspects of eicosanoid signaling. | Zhao, Y., Alexandre, C., Kelly, G., Vincent, J. P., Perez-Mockus, G. (2025). HIF-1alpha-mediated feedback prevents TOR signalling from depleting oxygen supply and triggering stress during normal development. Nat Commun, PubMed ID: 41423448
Summary: Growth deceleration before growth termination is a universal feature of growth during development. Transcriptomics analysis reveals that during their two-day period of growth deceleration, wing imaginal discs of Drosophila undergo a progressive metabolic shift from oxidative phosphorylation towards glycolysis. Ultra-sensitive reporters of HIF-1alpha stability and activity show that imaginal discs become increasingly hypoxic during development in normoxic conditions, suggesting that limiting oxygen supply could underlie growth deceleration. This study confirm the expectation that rising levels of HIF-1alpha dampen TOR signalling activity through transcriptional activation of REDD1 (Scylla and Charybdis) . Conversely, excess TOR leads, in a tissue-size-dependent manner, to hypoxia, which boosts HIF-1alpha levels and activity. Thus, HIF-1alpha mediates a negative feedback loop whereby TOR signalling triggers hypoxia, which in turn reduces TOR signalling. Abrogation of this feedback by Sima/HIF-1alpha knockdown leads to cellular stress, which is alleviated by reduced TOR signalling or a modest increase in environmental oxygen. It is concluded that Sima/HIF-1alpha prevents TOR-mediated growth from depleting local oxygen supplies during normal development. |
| Medina, A. B., Perochon, J., Tian, Y., Johnson, C. T., Holcombe, J., Ramesh, P., Polcownuk, S., Yu, Y., Cordero, J. B. (2025). Neuroendocrine control of intestinal regeneration through the vascular niche in Drosophila. Dev Cell, 60(22):3085-3101 e3086 PubMed ID: 40695286
Summary: Robust and controlled intestinal regeneration involves reciprocal interactions between the intestinal epithelium and its microenvironment. This study identifed signaling between enteroendocrine (EE) cells, vasculature-like trachea, and neurons, which drives regional and global stem cell proliferation during adult intestinal regeneration in Drosophila. Reactive oxygen species (ROS) from midgut cells promote production and secretion of diuretic hormone 31 (Dh31), from anterior midgut enteroendocrine (EE) cells. EE and neuronal Dh31 activate tracheal Dh31 receptor, leading to the production of the vascular endothelial growth factor (VEGF)- and platelet-derived-growth-factor (PDGF)-like ligand Pvf1. Pvf1 induces tracheal remodeling and intestinal stem cell (ISC) proliferation through autocrine and paracrine Pvr/mitogen-activated protein kinase (MAPK) signaling, respectively. While EE Dh31 exerts broad control of ISC proliferation throughout the midgut, effects of the neuronal source of the ligand appear restricted to the posterior midgut. Collectively,this work discovered an EE/neuronal/vascular signaling network, controlling global and domain-specific ISC proliferation during adult intestinal regeneration. | Ahrentlov, N., Kubrak, O., Lassen, M., Malita, A., Koyama, T., Frederiksen, A. S., Sigvardsen, C. M., John, A., Madsen, P. E. H., Halberg, K. V., Nagy, S., Imig, C., Richter, E. A., Texada, M. J., Rewitz, K. (2025). Protein-responsive gut hormone tachykinin directs food choice and impacts lifespan. Nat Metab, 7(6):1223-1245 PubMed ID: 40229448
Summary: Animals select food based on hungers that reflect dynamic macronutrient needs, but the hormonal mechanisms underlying nutrient-specific appetite regulation remain poorly defined. This study identified tachykinin (Tk) as a protein-responsive gut hormone in Drosophila and female mice, regulated by conserved environmental and nutrient-sensing mechanisms. Protein intake activates Tk-expressing enteroendocrine cells (EECs), driving the release of gut Tk through mechanisms involving target of rapamycin (TOR) and transient receptor potential A1 (TrpA1). In flies, this study delineated a pathway by which gut Tk controls selective appetite and sleep after protein ingestion, mediated by glucagon-like adipokinetic hormone (AKH) signalling to neurons and adipose tissue. This mechanism suppresses protein appetite, promotes sugar hunger and modulates wakefulness to align behaviour with nutritional needs. Inhibiting protein-responsive gut Tk prolongs lifespan through AKH, revealing a role for nutrient-dependent gut hormone signalling in longevity. These results provide a framework for understanding EEC-derived nutrient-specific satiety signals and the role of gut hormones in regulating food choice, sleep and lifespan. |
Wednesday January 21st - Transcriptional Regulation |
| Chen, X., Yan, X., Jing, C., Fu, B., Jin, W., Zhang, S., Wang, M., Liu, F., Sun, L. (2025). Ginsenoside Rc maintains sleep rhythm homeostasis by alleviating oxidative stress. Phytomedicine, 141:156634 PubMed ID: 40203472
Summary: Sleep disorders significantly impact physical health and quality of life. However, the current treatment strategies have several limitations. Panax ginseng (known as Asian ginseng, Korean ginseng, or Chinese ginseng) has been traditionally employed to calm the mind, but its active components and their mechanisms remain elusive. This study aimed to elucidate the sleep-improving actions of Panax ginseng active component, ginseng Rc, and its potential mechanisms. Sleep duration and rhythm of Drosophila were assessed via a behavior analysis system. Furthermore, the potential addictive side effects of ginsenoside Rc were assessed through capillary ingestion. Changes in mRNA levels of core clock genes and stress response-related genes were determined via RT-qPCR. In addition, the potential mechanisms underlying the efficacy of ginsenoside Rc were evaluated by transcriptomic methodologies. A molecular operating environment (MOE)-Dock simulation was conducted to predict the binding affinity between Pink1 and ginsenoside Rc and verified by surface plasmon resonance. Lastly, Western blotting was carried out to assess Sir2 expression and acetylation of brain proteins. It was observed that ginsenoside Rc improved sleep duration, latency, fragmentation, and amplitude. Furthermore, it upregulated the expression of the clock gene and was not addictive or dependency-inducing. Moreover, it increased antioxidant-related gene expression and reduced stress-related gene expression. In addition, transcriptomic analysis demonstrated that ginsenoside Rc also upregulated autophagy-related genes. Mechanistic studies showed that it improves sleep homeostasis by activating the Pink1/Sir2 signaling pathway, reducing oxidative stress, and modulating protein acetylation levels. This study identified ginsenoside Rc, a novel compound from ginseng, and revealed that it can maintain sleep homeostasis. Mechanistically, ginsenoside Rc alleviated oxidative stress by targeting Pink1 and Sir2. These findings provide evidence for the potential clinical application of ginsenoside Rc for treating sleep disorders. | Iwasaki, K., Neuhauser, C., Stokes, C., Rayshubskiy, A. (2025). The fruit fly, Drosophila melanogaster, as a microrobotics platform. Proc Natl Acad Sci U S A, 122(15):e2426180122 PubMed ID: 40198707
Summary: Engineering small autonomous agents capable of operating in the microscale environment remains a key challenge, with current systems still evolving. This study explores the fruit fly, Drosophila melanogaster, a classic model system in biology and a species adept at microscale interaction, as a biological platform for microrobotics. Initially, this study focuses on remotely directing the walking paths of fruit flies in an experimental arena. This was acclompished through two distinct approaches: harnessing the fruit flies' optomotor response and optogenetic modulation of its olfactory system. These techniques facilitate reliable and repeated guidance of flies between arbitrary spatial locations. Flies were guided along predetermined trajectories, enabling them to scribe patterns resembling textual characters through their locomotion. Olfactory-guided navigation was enhanced through additional optogenetic activation of attraction-inducing mushroom body output neurons. This control was extended to collective behaviors in shared spaces and navigation through constrained maze-like environments. The guidance technique was furher used to enable flies to carry a load across designated points in space, establishing the upper bound on their weight-carrying capabilities. Additionally, it was demonstrated that visual guidance can facilitate novel interactions between flies and objects, showing that flies can consistently relocate a small spherical object over significant distances. Last, it was demonstrated multiagent formation control, with flies alternating between distinct spatial patterns. Beyond expanding tools available for microrobotics, these behavioral contexts can provide insights into the neurological basis of behavior in fruit flies. |
| Deal, S. L., Bei, D., Gibson, S. B., Delgado-Seo, H., Fujita, Y., Wilwayco, K., Seto, E. S., Yamamoto, S. (2025). RNAi-based screen for pigmentation in Drosophila melanogaster reveals regulators of brain dopamine and sleep. bioRxiv, PubMed ID: 40236063
Summary: The dopaminergic system has been extensively studied for its role in behavior in animals as well as human neuropsychiatric and neurological diseases. However, little is known about how dopamine levels are tightly regulated in vivo. To identify novel regulators of dopamine, Drosophila melanogaster cuticle pigmentation was used as a readout, where dopamine is a precursor to melanin. We measured dopamine from genes known to be critical for cuticle pigmentation and performed an RNAi-based screen to identify new regulators of pigmentation. 153 potential pigmentation genes were found that were enriched for conserved homologs and disease- associated genes as well as developmental signaling pathways and mitochondria-associated proteins. From 35 prioritized candidates, 10 were fpimd to cause significant reduction in head dopamine levels and one caused an increase. Two genes, clueless and mask (multiple ankyrin repeats single KH domain), upon knockdown, reduced dopamine levels in the brain. Further examination suggests that Mask regulates the transcription of the rate-limiting dopamine synthesis enzyme, tyrosine hydroxylase, and its knockdown causes dopamine-dependent sleep phenotypes. In summary, by studying genes that affect cuticle pigmentation, a phenotype seemingly unrelated to the nervous system, it was possible to identify several genes that affect dopamine metabolism as well as a novel regulator of behavior. | Benoit, J. B., Bose, J., Ajayi, O. M., Webster, A., Grieshop, K., Lewis, D., Talbott, H., Polak, M. (2025). Shifted levels of sleep and activity during the night as mechanisms underlying ectoparasite resistance. NPJ Biol Timing Sleep, 2(1):15 PubMed ID: 40191448
Summary: Parasites harm host fitness and are pervasive agents of natural selection capable of driving the evolution of host resistance traits. previous work demonstrated evolutionary responses to artificial selection for increasing behavioral immunity to Gamasodes queenslandicus mites for Drosophila melanogaster. This study reports transcriptional shifts in metabolic processes due to selection for mite resistance. Dcreased starvation resistance and increased use of nutrient reserves in flies from mite-resistant lines were demonstrated. Resistant lines exhibited increased activity, reduced sleep, and elevated oxygen consumption during the night. Using a panel of D. melanogaster lines exhibiting variable sleep durations, a positive correlation was found between mite resistance and reduced sleep. Restraining the activity of artificially selected mite-resistant flies during exposure to parasites reduced their resistance advantage relative to control flies. The results suggest that ectoparasite resistance in this system involves increased activity during the scotophase (the dark portion of a photoperiod cycle) and metabolic gene expression at the expense of starvation resistance. |
| Cui, T., Wang, T. (2025). Exact box-counting and temporal sampling algorithms for fractal dimension estimation with applications to animal behavior analysis. Results Eng, 25 PubMed ID: 40230598
Summary: Fractal dimension (FD) is a widely recognized metric in mathematics and physics for quantifying the complexity of intricate objects and processes. Tis study proposes novel algorithms to estimate the FD of animal movement using high-resolution spatial and temporal data. To enhance estimation accuracy, an oversampling technique was developed that linearly interpolates between adjacent points on movement paths. Furthermore, an exact box-counting algorithm was introduced, tailored for piecewise linear paths, ensuring accurate fractal dimension estimations. Considering that animal behavior is typically recorded at fixed frame rates, a temporal sampling method was also proposed for calculating FD using temporal domain scales. Recognizing that FD varies with scale, a dual total least squares method was employed to identify the optimal scale for FD comparisons across different genotypes. Through large-scale experiments on the movement of Drosophila melanogaster larvae, mutations were showed in the schizophrenia-associated gene Dysbindin significantly increase FD, suggesting potential impairments in motor function. These findings highlight FD as a robust and quantitative metric for assessing the complexity of movement behavior. | Bath, E., Gleason, J. (2025). Is variation in female aggressiveness across Drosophila species associated with reproductive potential?. Proc Biol Sci, 292(2044):20242301 PubMed ID: 40199353
Summary: Aggression is a key determinant of fitness in many species, mediating access to mates, food and breeding sites. Variation in intrasexual aggression across species is likely to be driven by variation in resource availability and distribution. While males primarily compete over access to mates, females are likely to compete over resources to maximize offspring quantity and/or quality, such as food or breeding sites. To date, however, most studies have focused on male aggression, and little is known about drivers of female aggression across species. To investigate potential reproductive drivers of female aggression, the relationship between three reproductive traits and aggression was tested in eight Drosophila species. Using machine learning classifiers developed for Drosophila melanogaster, aggressive behaviours displayed in the presence of yeast for mated and unmated females. Female aggression was correlated with ovariole number across species, suggesting that females who lay more eggs are more aggressive. A need for resources for egg production or oviposition sites may therefore be drivers of female aggression, though other potential hypotheses are discussed. |
Tuesday January 27th - Evolution |
| Lai, W. Y., Hsu, S. K., Futschik, A., Schlotterer, C. (2025). Pleiotropy increases parallel selection signatures during adaptation from standing genetic variation. Elife, 13 PubMed ID: 40227842
Summary: The phenomenon of parallel evolution, whereby similar genomic and phenotypic changes occur across replicated pairs of populations or species, is widely studied. Nevertheless, the determining factors of parallel evolution remain poorly understood. Theoretical studies have proposed that pleiotropy, the influence of a single gene on multiple traits, is an important factor. In order to gain a deeper insight into the role of pleiotropy for parallel evolution from standing genetic variation, this study characterized the interplay between parallelism, polymorphism, and pleiotropy. The present study examined the parallel gene expression evolution in 10 replicated populations of Drosophila simulans, which were adapted from standing variation to the same new temperature regime. The data demonstrate that the parallel evolution of gene expression from standing genetic variation is positively correlated with the strength of pleiotropic effects. The ancestral variation in gene expression is, however, negatively correlated with parallelism. Given that pleiotropy is also negatively correlated with gene expression variation, a causal analysis was conducted to distinguish cause and correlation and evaluate the role of pleiotropy (a genetic phenomenon where a single gene influences multiple, seemingly unrelated phenotypic traits, often because the gene's product is used in various cells or pathwaysa genetic phenomenon where a single gene influences multiple, seemingly unrelated phenotypic traits, often because the gene's product is used in various cells or pathways). The causal analysis indicated that both direct (causative) and indirect (correlational) effects of pleiotropy contribute to parallel evolution. The indirect effect is mediated by historic selective constraint in response to pleiotropy. This results in parallel selection responses due to the reduced standing variation of pleiotropic genes. The direct effect of pleiotropy is likely to reflect a genetic correlation among adaptive traits, which in turn gives rise to synergistic effects and higher parallelism. | Glaser-Schmitt, A., Lebherz, M., Saydam, E., Bornberg-Bauer, E., Parsch, J. (2025). Expression of De Novo Open Reading Frames in Natural Populations of Drosophila melanogaster. J Exp Zool B Mol Dev Evol, PubMed ID: 40231390
Summary: De novo genes, which originate from noncoding DNA, are known to have a high rate of turnover over short evolutionary timescales, such as within a species. Thus, their expression is often lineage- or genetic background-specific. However, little is known about their levels and breadth of expression as populations of a species diverge. This study utilized publicly available RNA-seq data to examine the expression of newly evolved open reading frames (neORFs) in comparison to non- and protein-coding genes in Drosophila melanogaster populations from the derived species range in Europe and the ancestral range in sub-Saharan Africa. These datasets included two adult tissue types as well as whole bodies at two temperatures for both sexes and three larval/prepupal developmental stages in a single tissue and sex, which allowed examining neORF expression and divergence across multiple sample types as well as sex and population. A relatively large proportion (approximately 50%) was detected of annotated neORFs as expressed in the population samples, with neORFs often showing greater expression divergence between populations than non- or protein-coding genes. However, differential expression of neORFs between populations tended to occur in a sample type-specific manner. On the other hand, neORFs displayed less sex-biased expression than the other two gene classes, with the majority of sex-biased neORFs detected in whole bodies, which may be attributable to the presence of the gonads. neORFs were found to be shared among multiple lines in the original set of inbred lines in which they were first detected were more likely to be both expressed and differentially expressed in the new population samples, suggesting that neORFs at a higher frequency (i.e. present in more individuals) within a species are more likely to be functional. |
| Blair, L. K., Cridland, J. M., Luo, Y., Begun, D. J., Kopp, A. (2025). Improved sampling of genotypes and species reveals new insights on de novo gene history and regulatory origins. Genetics, 230(2) PubMed ID: 40250972
Summary: The evolution of genes de novo from ancestrally nongenic sequences may be a significant mechanism of gene origin. Many studies have focused on identifying de novo genes in distant evolutionary comparisons, which bias the sample of de novo genes toward older genes that have acquired important functions and have been retained and refined by selection. This report focuses on the earliest steps in de novo gene origin by identifying young, polymorphic transcripts that may be missed by other study designs. To accomplish this, we sequenced tissue transcriptomes from a much larger sample of genotypes than have been used in previous analyses of de novo genes in Drosophila melanogaster. 90 potential species-specific de novo genes were identified expressed in the male accessory glands of 29 D. melanogaster lines derived from the same natural population. Most young transcripts were found to be both rare in the population and transcribed at low abundance. Improved sampling of both ingroup and outgroup genotypes reveals that many young genes are polymorphic in more than 1 species, resulting in substantial uncertainty about the age and phylogenetic distribution of de novo genes. Among the genes expressed in the same tissue, gene age correlates with proximity to other tissue-specific genes, with the youngest genes being least likely to occur near established tissue-specific genes. This and other lines of evidence suggest that de novo genes do not commonly evolve by simply reutilizing preexisting regulatory elements. Together, these results provide new insights into the origin and early evolution of de novo genes. | Hey, J., Pavinato, V. A. C. (2025). Isolating selective from non-selective forces using site frequency ratios. PLoS Genet, 21(4):e1011427 PubMed ID: 40258089
Summary: A new method is introduced for estimating the distribution of mutation fitness effects using site frequency spectra. Unlike previous methods, which make assumptions about non-selective factors, or that try to incorporate such factors into the underlying model, this new method mostly avoids non-selective effects by working with the ratios of counts of selected sites to neutral sites. An expression for the likelihood of a set of selected/neutral ratios is found by treating the ratio of two Poisson random variables as the ratio of two gaussian random variables. This approach also avoids the need to estimate the relative mutation rates of selected and neutral sites. Simulations over a wide range of demographic models, with linked selection effects show that the new SFRatios method (a behavioral technique used to quantify food intake by measuring the feeding frequency [proboscis-extension) of flies], performs well for statistical tests of selection, and it performs well for estimating the distribution of selection effects. Performance was better with weak selection models and for expansion and structured demographic models than for bottleneck models. Applications to two populations of Drosophila melanogaster reveal clear but very weak selection on synonymous sites. For nonsynonymous sites, selection was found to be consistent with previous estimates and stronger for an African population than for one from North Carolina. |
| Audet, T., Wilson, A., Dukas, R., Dworkin, I. (2025). The role of resource defensibility in facilitating sexually-selected weapon evolution: An experimental evolution test. Evolution, PubMed ID: 40201973
Summary: Animal weapons have evolved multiple times primarily for battling for access to mates. Despite intra-sexual selection being common, exaggerated weapons have evolved relatively rarely. So why do exaggerated weapons not evolve more commonly? It has been hypothesized that three conditions are necessary for evolution of exaggerated weapons: high variance in reproductive success, patchy, high-value resources, and spatial environments conducive to one-on-one competition. Here, we test this hypothesis by performing experimental evolution in Drosophila melanogaster, utilizing heterogeneous environments where conditions facilitating territorial defense and opportunities for competitive interactions vary. We examine changes in sexually dimorphic morphology and male aggression that are predicted to occur, based on this model. Whether condition dependence for sexual dimorphism has evolved after 35 and 75 generations of experimental evolution was studied. Aggression did increase, albeit modestly, in environments that facilitate resource defense. Morphological changes are modest although with some trait specific changes to allometry, generally in the opposite direction of this study's predictions. Condition dependence trends in the opposite direction from those predicted by the hypothesis as well. The results are discussed in the context of the necessary conditions for the evolution of exaggerated weapons, and if, and when condition dependence may evolve. | Arnce, L. R., Bubnell, J. E., Aquadro, C. F. (2025). Comparative Analysis of Drosophila Bam and Bgcn Sequences and Predicted Protein Structural Evolution. J Mol Evol, 93(2):278-291 PubMed ID: 40178596
Summary: The protein encoded by the Drosophila melanogaster gene bag of marbles (bam) plays an essential role in early gametogenesis by complexing with the gene product of benign gonial cell neoplasm (bgcn) to promote germline stem cell daughter differentiation in males and females. This study compared the AlphaFold2 and AlphaFold Multimer predicted structures of Bam protein and the Bam:Bgcn protein complex between D. melanogaster, D. simulans, and D. yakuba, where bam is necessary in gametogenesis to that in D. teissieri, where it is not. Despite significant sequence divergence, very little evidence was found of significant structural differences in high confidence regions of the structures across the four species. This suggests that Bam structure is unlikely to be a direct cause of its functional differences between species and that Bam may simply not be integrated in an essential manner for GSC differentiation in D. teissieri. Patterns of positive selection and significant amino acid diversification across species is consistent with the Selection, Pleiotropy, and Compensation (SPC) model, where detected selection at bam is consistent with adaptive change in one major trait followed by positively selected compensatory changes for pleiotropic effects (in this case perhaps preserving structure). In the case of bam, The major trait could be genetic interaction with the endosymbiotic bacteria Wolbachia pipientis. Following up on detected signals of positive selection and comparative structural analysis could provide insight into the distribution of a primary adaptive change versus compensatory changes following a primary change. |
Thursday, January 15th - Disease Models |
| Huang, Y. C., Costa, C. A. M., Ruiz, N. V., Wang, X., Jevitt, A., Breneman, C. M., Han, C., Deng, W. M. (2025). Polyploidy promotes transformation of epithelial cells into non-professional phagocytes. bioRxiv, PubMed ID: 40196694
Summary: Removal of dead and damaged cells is critical for organismal health. Under stress conditions such as nutritional deprivation, infection, or temperature shift, the clearance of nonessential cells becomes a universal strategy to conserve energy and maintain tissue homeostasis. Typically, this task is performed by professional phagocytes such as macrophages. However, non-professional phagocytes (NPPs) can also adopt a phagocytic fate under specific circumstances. Similar to professional phagocytes, NPPs undergo transitions from immature to mature states and activation, but the precise cellular and molecular mechanisms governing their maturation, induction and phagocytic execution remain largely unknown. A notable example of stress-induced phagocytosis is the removal of germline cells by follicle cell-derived NPPs during oogenesis in Drosophila. This study reports that the transformation of follicle cells into NPPs is dependent on Notch signaling activation during mid-oogenesis. Moreover, Notch overactivation is sufficient to trigger germline cell death and clearance (GDAC). It was further shown that polyploidy, driven by Notch signaling-induced endoreplication, is essential for the transformation of follicle cells into NPPs. Polyploidy facilitates the activation of JNK signaling, which is crucial for the phagocytic behavior of these cells. Additionally, polyploidy in epidermal cells, another type of NPPs, is shown to be important for their engulfment of dendrites during induced degeneration. Together, these findings suggest that polyploidy is a critical factor in the transformation of epithelial cells into NPPs, enabling their phagocytic functions, which are essential for maintaining cellular and organismal homeostasis during stress conditions. | Singh, J., Verma, D., Sarkar, B., Paul, M. S., Mutsuddi, M., Mukherjee, A. (2025). Notch and LIM-homeodomain protein Arrowhead regulate each other in a feedback mechanism to play a role in wing and neuronal development in Drosophila. Open Biol, 15(4):240247 PubMed ID: 40300650
Summary: The Notch pathway is an evolutionarily conserved signalling system that operates to influence an astonishing array of cell fate decisions in different developmental contexts. To identify novel effectors of Notch signalling, this study analysed the whole transcriptome of Drosophila wing and eye imaginal discs in which an activated form of Notch was overexpressed. A LIM-homeodomain protein, Arrowhead (Awh), was identified as a novel candidate that plays a crucial role in Notch-mediated developmental events. Awh alleles show strong genetic interaction with Notch pathway components. Awh loss-of-function upregulates Notch targets Cut and Wingless. Awh gain-of-function downregulates Notch targets by reducing the expression of the ligand Delta. Consequently, the expression of the Wingless effector molecule Armadillo and its downstream targets, Senseless and Vestigial, also gets downregulated. Awh overexpression leads to ectopic expression of engrailed, a segment polarity gene in the anterior region of wing disc, leading to patterning cdefects. Additionally, Notch gain-of-function-mediated neuronal defects get significantly rescued with Awh overexpression. Activated Notch inhibits Awh activity, suggesting a regulatory loop between Awh and Notch. Additionally, the defects caused by Awh gain-of-function were remarkably rescued by Chip, a LIM interaction domain containing transcriptional co-factor. The present study highlights the novel feedback regulation between Awh and Notch. |
| Fujinaga, D., Nolan, C., Yamanaka, N. (2025). Functional characterization of eicosanoid signaling in Drosophila development. PLoS Genet, 21(5):e1011705 PubMed ID: 40344083
Summary: 20-carbon fatty acid-derived eicosanoids are versatile signaling oxylipins in mammals. In particular, a group of eicosanoids termed prostanoids are involved in multiple physiological processes, such as reproduction and immune responses. Although some eicosanoids such as prostaglandin E2 (PGE2) have been detected in some insect species, molecular mechanisms of eicosanoid synthesis and signal transduction in insects have not been thoroughly investigated. Phylogenetic analysis indicated that, in clear contrast to the presence of numerous receptors for oxylipins and other lipid mediators in humans, the Drosophila genome only possesses a single ortholog of such receptors, which is homologous to human prostanoid receptors. This G protein-coupled receptor, named Prostaglandin Receptor or PGR, is activated by PGE2 and its isomer PGD2 in Drosophila S2 cells. PGR mutant flies die as pharate adults with insufficient tracheal development, which can be rescued by supplying high oxygen. Consistent with this, through a comprehensive mutagenesis approach, this study identified a Drosophila PGE synthase whose mutants show similar pharate adult lethality with hypoxia responses. Drosophila thus has a highly simplified eicosanoid signaling pathway as compared to humans, and it may provide an ideal model system for investigating evolutionarily conserved aspects of eicosanoid signaling. | Zhao, Y., Alexandre, C., Kelly, G., Vincent, J. P., Perez-Mockus, G. (2025). HIF-1alpha-mediated feedback prevents TOR signalling from depleting oxygen supply and triggering stress during normal development. Nat Commun, PubMed ID: 41423448
Summary: Growth deceleration before growth termination is a universal feature of growth during development. Transcriptomics analysis reveals that during their two-day period of growth deceleration, wing imaginal discs of Drosophila undergo a progressive metabolic shift from oxidative phosphorylation towards glycolysis. Ultra-sensitive reporters of HIF-1alpha stability and activity show that imaginal discs become increasingly hypoxic during development in normoxic conditions, suggesting that limiting oxygen supply could underlie growth deceleration. This study confirm the expectation that rising levels of HIF-1alpha dampen TOR signalling activity through transcriptional activation of REDD1 (Scylla and Charybdis) . Conversely, excess TOR leads, in a tissue-size-dependent manner, to hypoxia, which boosts HIF-1alpha levels and activity. Thus, HIF-1alpha mediates a negative feedback loop whereby TOR signalling triggers hypoxia, which in turn reduces TOR signalling. Abrogation of this feedback by Sima/HIF-1alpha knockdown leads to cellular stress, which is alleviated by reduced TOR signalling or a modest increase in environmental oxygen. It is concluded that Sima/HIF-1alpha prevents TOR-mediated growth from depleting local oxygen supplies during normal development. |
| Medina, A. B., Perochon, J., Tian, Y., Johnson, C. T., Holcombe, J., Ramesh, P., Polcownuk, S., Yu, Y., Cordero, J. B. (2025). Neuroendocrine control of intestinal regeneration through the vascular niche in Drosophila. Dev Cell, 60(22):3085-3101 e3086 PubMed ID: 40695286
Summary: Robust and controlled intestinal regeneration involves reciprocal interactions between the intestinal epithelium and its microenvironment. This study identifed signaling between enteroendocrine (EE) cells, vasculature-like trachea, and neurons, which drives regional and global stem cell proliferation during adult intestinal regeneration in Drosophila. Reactive oxygen species (ROS) from midgut cells promote production and secretion of diuretic hormone 31 (Dh31), from anterior midgut enteroendocrine (EE) cells. EE and neuronal Dh31 activate tracheal Dh31 receptor, leading to the production of the vascular endothelial growth factor (VEGF)- and platelet-derived-growth-factor (PDGF)-like ligand Pvf1. Pvf1 induces tracheal remodeling and intestinal stem cell (ISC) proliferation through autocrine and paracrine Pvr/mitogen-activated protein kinase (MAPK) signaling, respectively. While EE Dh31 exerts broad control of ISC proliferation throughout the midgut, effects of the neuronal source of the ligand appear restricted to the posterior midgut. Collectively,this work discovered an EE/neuronal/vascular signaling network, controlling global and domain-specific ISC proliferation during adult intestinal regeneration. | Ahrentlov, N., Kubrak, O., Lassen, M., Malita, A., Koyama, T., Frederiksen, A. S., Sigvardsen, C. M., John, A., Madsen, P. E. H., Halberg, K. V., Nagy, S., Imig, C., Richter, E. A., Texada, M. J., Rewitz, K. (2025). Protein-responsive gut hormone tachykinin directs food choice and impacts lifespan. Nat Metab, 7(6):1223-1245 PubMed ID: 40229448
Summary: Animals select food based on hungers that reflect dynamic macronutrient needs, but the hormonal mechanisms underlying nutrient-specific appetite regulation remain poorly defined. This study identified tachykinin (Tk) as a protein-responsive gut hormone in Drosophila and female mice, regulated by conserved environmental and nutrient-sensing mechanisms. Protein intake activates Tk-expressing enteroendocrine cells (EECs), driving the release of gut Tk through mechanisms involving target of rapamycin (TOR) and transient receptor potential A1 (TrpA1). In flies, this study delineated a pathway by which gut Tk controls selective appetite and sleep after protein ingestion, mediated by glucagon-like adipokinetic hormone (AKH) signalling to neurons and adipose tissue. This mechanism suppresses protein appetite, promotes sugar hunger and modulates wakefulness to align behaviour with nutritional needs. Inhibiting protein-responsive gut Tk prolongs lifespan through AKH, revealing a role for nutrient-dependent gut hormone signalling in longevity. These results provide a framework for understanding EEC-derived nutrient-specific satiety signals and the role of gut hormones in regulating food choice, sleep and lifespan. |
Wednesday January 21st - Transcriptional Regulation |
| Evdokimova, A. A., Kolesnikova, T. D., Mazina, M. Y., Krasnov, A. N., Erokhin, M., Chetverina, D., Vorobyeva, N. E. (2025). Transcriptional induction by ecdysone in Drosophila salivary glands involves an increase in chromatin accessibility and acetylation. Nucleic Acids Res, 53(7) PubMed ID: 40239993
Summary: Transcriptional activation by 20-hydroxyecdysone (20E) in Drosophila provides an excellent model for studying tissue-specific responses to steroids. An increase in the 20E concentration regulates the degradation of larval and the proliferation of adult tissues during metamorphosis. To study 20E-dependent transcription, the natural system was used for controlling the 20E concentration-the E23 membrane transporter- which exports 20E from the cell. E23 was artificially expressed in tissues to suppress the first wave of 20E-inducible transcription at metamorphosis. E23 expression revealed a plethora of 20E-dependent genes in alivary glands, while mildly affecting transcription in brain. The mechanisms are described controlling transcriptional activation by 20E in salivary glands. 20E depletion decreased the binding of Pol II and the TFIID subunit, TBP, to the promoters of primary targets, demonstrating the role of 20E in transcription initiation. At target loci, 20E depletion resulted in the malfunctioning of sites co-bound with EcR and CBP/Nejire and enriched for the mark inherent to active enhancers. At these sites, the 20E concentration was found to control chromatin accessibility and acetylation. It is suggested that the activity of these 'active' ecdysone-sensitive elements was responsible for the active status of 20E targets in the salivary glands of wandering larvae. | Dahn, S., Wagner, A. E. (2025). Drosophila melanogaster as a model organism to investigate sex specific differences. Sci Rep, 15(1):19648 PubMed ID: 40467909
Summary: Sex differences in physiology, anatomy, behavior, and genetics are well-documented throughout the animal kingdom. These differences are often neglected in research. This imbalance can have detrimental effects, as seen in cases where certain drugs have stronger side effects in females than in males. The fruit fly, Drosophila melanogaster, presents a promising model for studying these sex-specific differences because it shares many disease-related genes and is easy to use. RNA of 10-day-old and 30-day-old D. melanogaster (w1118) was isolated and sequenced. In 10-day-old flies 3969 genes are significantly higher expressed in males than in females, and 7176 genes are significantly lower expressed in males. In 30-day-old males 3735 genes are significantly higher expressed than in females, and 7101 genes are significantly lower expressed. In detail, the present study shows that male flies exhibit higher expression levels of genes involved in toll signaling, Imd signaling, insulin signaling, and lipid metabolism. These findings highlight D. melanogaster as a valuable model organism for studying sex differences in these highly conserved signaling pathways. This model could help analyzing the sex-specific effects of dietary interventions or drugs, ultimately leading to a better understanding of sex-specific interconnections and improving the development of more effective, sex-specific medical treatments. |
| Sun, Y., Shui, K., Li, Q., Liu, C., Jin, W., Ni, J. Q., Lu, J., Zhang, L. (2025). Upstream open reading frames dynamically modulate CLOCK protein translation to regulate circadian rhythms and sleep. PLoS Biol, 23(5):e3003173 PubMed ID: 40354412
Summary: The circadian rhythm is an evolutionarily conserved mechanism with translational regulation increasingly recognized as pivotal in its modulation. This study found that upstream open reading frames (uORFs) are enriched in Drosophila circadian rhythm genes, with particularly conserved uORFs present in core circadian clock genes. Evidence is presented that the uORFs of the core clock gene, Clock (Clk), rhythmically and substantially attenuate CLK protein translation in Drosophila, with pronounced suppression occurring during daylight hours. Eliminating Clk uORFs leads to increased CLK protein levels during the day and results in a shortened circadian cycle, along with a broad shift in clock gene expression rhythms. Notably, Clk uORF deletion also augments morning sleep by reducing dopaminergic activity. Beyond daily circadian adjustments, Clk uORFs play a role in modulating sleep patterns in response to seasonal daylight variations. Furthermore, the Cl uORFs act as an important regulator to shape the rhythmic expression of a vast array of genes and influence multifaceted physiological outcomes. Collectively, this research sheds light on the intricate ways uORFs dynamically adjust downstream coding sequences to acclimate to environmental shifts. | Fallacaro, S., Mukherjee, A., Turner, M. A., Garcia, H. G., Mir, M. (2025). Transcription factor hubs exhibit gene-specific properties that tune expression. bioRxiv, PubMed ID: 40291650
Summary: The spatial and temporal control of gene expression relies on transcription factors binding to and occupying their target sites. Transcription factor hubs-localized, high-concentration microenvironments-promote transcription by facilitating binding and recruitment of transcriptional machinery and co-factors. Hubs are often thought to have emergent nucleus-wide properties depending on transcription factor nuclear concentrations and intrinsic, protein sequence-dependent properties. This global model does not account for gene-specific hub regulation. Using high-resolution lattice light-sheet microscopy in Drosophila embryos, hubs formed by the morphogen transcription factor, Dorsal, was examined at reporter genes with distinct enhancer compositions. snail was found to recruit long-lived, high-intensity hubs; sog exhibits shorter-lived, lower-intensity hubs; and hunchback, lacking Dorsal binding sites, shows only transient hub interactions. Hub intensity and interaction duration correlate with burst amplitude, RNAPII loading rate, and transcriptional output. These findings challenge the global view of hub formation and support a model where hub properties are locally tuned in a gene-specific manner to regulate transcriptional kinetics. |
| Kemp, J. P., Jr., Geisler, M. S., Hoover, M., Cho, C. Y., O'Farrell, P. H., Marzluff, W. F., Duronio, R. J. (2025). Cell-cycle-regulated transcriptional pausing of Drosophila replication-dependent histone genes. Mol Biol Cell, 36(7):ar88 PubMed ID: 40397569
Summary: Coordinated expression of replication-dependent (RD) histones genes occurs within the Histone Locus Body (HLB) during S-phase, but the molecular steps in transcription that are cell-cycle regulated are unknown. We report that Drosophila RNA Pol II promotes HLB formation and is enriched in the HLB outside of S-phase, including G(1)-arrested cells that do not transcribe RD histone genes. In contrast, the transcription elongation factor Spt6 is enriched in HLBs only during S-phase. Proliferating cells in the wing and eye primordium express full-length histone mRNAs during S-phase but express only short nascent transcripts in cells in G(1) or G(2) consistent with these transcripts being paused and then terminated. Full-length transcripts are produced when Cyclin E/Cdk2 is activated as cells enter S-phase. Thus, activation of transcription elongation by Cyclin E/Cdk2 and not recruitment of RNA pol II to the HLB is the critical step that links histone gene expression to cell-cycle progression. | Chatsirisupachai, K., Moene, C. J. I., Kleinendorst, R., Kreibich, E., Molina, N., Krebs, A. (2025). Mouse promoters are characterised by low occupancy and high turnover of RNA polymerase II. Mol Syst Biol, 21(5):447-471 PubMed ID: 40164797
Summary: The general transcription machinery and its occupancy at promoters are highly conserved across metazoans. This contrasts with the kinetics of mRNA production that considerably differ between model species such as Drosophila and mouse. The molecular basis for these kinetic differences is currently unknown. This study used Single-Molecule Footprinting to measure RNA Polymerase II (Pol II) occupancy, the fraction of DNA molecules bound, at promoters in mouse and Drosophila cell lines. Single-molecule data reveals that Pol II occupancy is on average 3-5 times more frequent at transcriptionally active Drosophila promoters than active mouse promoters. Kinetic modelling of the occupancy states suggests that these differences in Pol II occupancy are determined by the ratio between the transcription initiation and Pol II turnover rates. Chemical perturbation of transcription initiation was used to determine Pol II turnover rate in both species. Integration of these data into the model shows that infrequent Pol II occupancy in mouse is explained by the combination of high Pol II turnover and low transcription initiation rates. |
Thursday, January 15th - Disease Models |
| Xiao, G., Li, Y., Hu, Y., Tan, K., Wang, M., Zhu, K., San, M., Cheng, Q., Tayier, D., Hu, T., Dang, P., Li, J., Cheng, C., Perrimon, N., Yang, Z., Song, W. (2025). Intratumor HIF-1alpha modulates production of a cachectic ligand to cause host wasting. Cell Insight, 4(3):100247 PubMed ID: 40336592
Summary: Tumor-host interactions play critical roles in cancer-associated cachexia. Previous studies have identified several cachectic proteins secreted by tumors that impair metabolic homeostasis in multiple organs, leading to host wasting. The molecular mechanisms by which malignant tumors regulate the production or secretion of these cachectic proteins, however, still remain largely unknown. This study used different Drosophila cachexia models to investigate how malignant tumors regulate biosynthesis of ImpL2, a conserved cachectic protein that inhibits systemic insulin/IGF signaling and suppresses anabolism of host organs. Through bioinformatic and biochemical analysis, this study found that hypoxia-inducible factor HIF-1&alpah;/Sima directly binds to the promoter region of ImpL2 gene for the first time, promoting its transcription in both tumors and non-tumor cells. Interestingly, expressing HphA to moderately suppress HIF-1&alpha/Sima activity in adult yki (3SA) gut tumors or larval scrib1 RasV12 disc tumors sufficiently decreased ImpL2 expression and improved organ wasting, without affecting tumor growth. This study further revealed conserved regulatory mechanisms conserved across species, as intratumor HIF-1α enhances the production of IGFBP-5, a mammalian homolog of fly ImpL2, contributing to organ wasting in both tumor-bearing mice and patients. Therefore, this study provides novel insights into the mechanisms by which tumors regulate production of cachectic ligands and the pathogenesis of cancer-induced cachexia. | Villalobos-Cantor, S., Arreola-Bustos, A., Martin, I. (2025). Genome-wide analysis reveals genes mediating resistance to paraquat neurodegeneration in Drosophila. Genetics, 230(3) PubMed ID: 40343931
Summary: Parkinson's disease (PD) is thought to develop through a complex interplay of genetic and environmental factors. Epidemiological studies have linked exposure to certain pesticides such as paraquat with elevated PD risk, although how a person's genetic makeup influences disease risk upon exposure remains unknown. Here, we used a genome-wide approach to uncover genes that play a role in resistance to paraquat-induced dopaminergic (DA) neurodegeneration in Drosophila. This study developed a paraquat exposure model displaying delayed-onset DA neurodegeneration to recapitulate this aspect of human disease. Genetic background proves to be a strong determinant of paraquat-induced DA neurodegeneration susceptibility across a series of nearly 200 fly strains called the Drosophila Genetic Reference Panel. Through unbiased genome-wide analysis and follow-up validation, two candidate paraquat resistance genes, luna and CG32264. In gene-level studies, decreased expression of luna or CG32264 is associated with paraquat-induced DA neuron loss while overexpression of either gene prevents neurodegeneration in vivo. The mammalian ortholog of CG32264 is Phactr2, which has previously been linked to idiopathic PD risk in several populations. Hence, these results reveal genes regulating paraquat-induced DA neuron loss that intersect with human PD risk variants, supporting the potential relevance of our findings to PD and underscoring a role for gene-environment interactions in pesticide-related DA neurodegeneration. |
| Adebambo, T. H., Medina-Flores, F., Zhang, S., Lerit, D. A. (2025). Arsenic impairs Drosophila neural stem cell mitotic progression and sleep behavior in a tauopathy model. G3 (Bethesda), 15(5) PubMed ID: 40192438
Summary: Despite established exposure limits, arsenic remains the most significant environmental risk factor detrimental to human health and is associated with carcinogenesis and neurotoxicity. Arsenic compromises neurodevelopment, and it is associated with peripheral neuropathy in adults. Exposure to heavy metals, such as arsenic, may also increase the risk of neurodegenerative disorders. Nevertheless, the molecular mechanisms underlying arsenic-induced neurotoxicity remain poorly understood. Elucidating how arsenic contributes to neurotoxicity may mitigate some of the risks associated with chronic sublethal exposure and inform future interventions. This study examined the effects of arsenic exposure on Drosophila larval neurodevelopment and adult neurologic function. Consistent with prior work, significant developmental delays and heightened mortality were identified in response to arsenic. Within the developing larval brain, a dose-dependent increase in brain volume was identified. This aberrant brain growth is coupled with impaired mitotic progression of the neural stem cells (NSCs), progenitors of the neurons and glia of the central nervous system. Live imaging of cycling NSCs reveals significant delays in cell cycle progression upon arsenic treatment, leading to genomic instability. In adults, chronic arsenic exposure reduces neurologic function, such as locomotion. Finally, arsenic selectively impairs circadian rhythms in a humanized tauopathy model. These findings inform mechanisms of arsenic neurotoxicity and reveal sex-specific and genetic vulnerabilities to sublethal exposure. | Bhatnagar, A., Thomas, C. M., Nge, G. G., Zaya, A., Dasari, R., Chongtham, N., Manandhar, B., Kortagere, S., Elefant, F. (2025). Tip60 HAT activators as therapeutic modulators for Alzheimer's disease. Nat Commun, 16(1):3347 PubMed ID: 40199891
Summary: Reduced histone acetylation in the brain causes transcriptional dysregulation and cognitive impairment that are key initial steps in Alzheimer's disease (AD) etiology. Unfortunately, current treatment strategies primarily focus on histone deacetylase inhibition (HDACi) that causes detrimental side effects due to non-specific acetylation. This study testd Tip60 histone acetyltransferase (HAT) activation as a therapeutic strategy for selectively restoring cognition-associated histone acetylation depleted in AD by developing compounds that enhance Tip60's neuroprotective HAT function. Several compounds show high Tip60-binding affinity predictions in silico, enhanced Tip60 HAT action in vitro, and restore Tip60 knockdown mediated functional deficits in Drosophila in vivo. Furthermore, compounds prevent neuronal deficits and lethality in an AD-associated amyloid precursor protein neurodegenerative Drosophila model and remarkably, restore expression of repressed neuroplasticity genes in the AD brain, underscoring compound specificity and therapeutic effectiveness. These results highlight Tip60 HAT activators as a promising therapeutic neuroepigenetic modulator strategy for AD treatment. |
| Toure, H., Durand, N., Orgeur, M., Galindo, L. A., Girard-Misguich, F., GuEnal, I., Herrmann, J. L., Szuplewski, S. (2025). ENaC is a host susceptibility factor to bacterial infections in cystic fibrosis context. Commun Biol, 8(1):653 PubMed ID: 40269088
Summary: Cystic fibrosis (CF) is a genetic disease caused by dysfunction in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) chloride channel. Patients with CF are hypersusceptible to Mycobacterium abscessus infection, a fast-growing mycobacterium and harmful opportunistic pathogen. Although CFTR dysfunction is known as a host susceptibility factor for M. abscessus infection, the functional impact of the trimeric Epithelial sodium Channel (ENaC), whose activity is negatively regulated by CFTR, towards M. abscessus infection has not been explored yet. To address this issue, advantage was taken of miR-263a deficient Drosophila presenting a CF-like phenotype due to ENaC hyperactivity (ENaC+). ENaC+ flies were as hypersusceptible to M. abscessus infection as the Cftr-deficient flies. The hypersensitivity of ENaC+ flies to M. abscessus infection was fully rescued by blocking ENaC hyperactivity, both chemically and genetically. Furthermore, ENaC hyperactivity per se was detrimental to ENaC+ Drosophila, as they were unable to mount an efficient humoral immune response. Upon infection, ENaC+ flies failed to upregulate 20-hydroxyecdysone production, which subsequently altered the production of protective antimicrobial peptides against M. abscessus. Overall, these results show that ENaC plays a key role in host susceptibility to M. abscessus infection and, correlatively to other CF pathogens. | Yan, J., Feng, C., Zhang, H., Luo, T., Chen, H., Chen, H. (2025). Dapagliflozin ameliorates intestinal stem cell aging by regulating the MAPK signaling pathway in Drosophila. Front Cell Dev Biol, 13:1576258 PubMed ID: 40337552
Summary: Intestinal stem cells (ISCs) possess the ability to self-renew and differentiate, which is essential for maintaining intestinal tissue homeostasis. However, their functionality significantly declines with age, leading to diminished tissue regeneration and an increased risk of age-associated diseases. This study investigates the effects of Dapagliflozin (DAPA), a novel insulin sensitizer and SGLT2 inhibitor, on aging ISCs using the Drosophila melanogaster model. The findings demonstrate that Dapagliflozin (Farxiga) DAPA can inhibit the MAPK signaling pathway, as confirmed by network pharmacology analysis and molecular docking experiments. DAPA ameliorates ISC aging, improves intestinal function (including enhanced fecal excretion, restored intestinal barrier integrity and acid-base balance), and enhances healthspan. These results highlight the potential of DAPA as an anti-aging therapeutic agent. This study provides new evidence for the application of DAPA as an anti-aging treatment. |
Wednesday, January 14th - Behavior |
| Brudner, S., Zhou, B., Jayaram, V., Santana, G. M., Clark, D. A., Emonet, T. (2025). Fly navigational responses to odor motion and gradient cues are tuned to plume statistics. bioRxiv, PubMed ID: 40235995
Summary: Odor cues guide animals to food and mates. Different environmental conditions can create differently patterned odor plumes, making navigation more challenging. Prior work has shown that animals turn upwind when they detect odor and cast crosswind when they lose it. Animals with bilateral olfactory sensors can also detect directional odor cues, such as odor gradient and odor motion. It remains unknown how animals use these two directional odor cues to guide crosswind navigation in odor plumes with distinct statistics. This problem was investigated theoretically and experimentally. These directional odor cues provide complementary information for navigation in different plume environments. We numerically analyzed real plumes to show that odor gradient cues are more informative about crosswind directions in relatively smooth odor plumes, while odor motion cues are more informative in turbulent or complex plumes. Neural networks trained to optimize crosswind turning converge to distinctive network structures that are tuned to odor gradient cues in smooth plumes and to odor motion cues in complex plumes. These trained networks improve the performance of artificial agents navigating plume environments that match the training environment. By recording Drosophila as they navigated different odor plume environments, this study verified that flies show the same correspondence between informative cues and plume types. Fly turning in the crosswind direction is correlated with odor gradients in smooth plumes and with odor motion in complex plumes. Overall, these results demonstrate that these directional odor cues are complementary across environments, and that animals exploit this relationship. | Philyaw, T. J., Titos, I., Cummins-Beebee, P. N., Rodan, A. R., Rothenfluh, A. (2025). Bitter Sensing Protects Drosophila from Developing Experience-Dependent Cocaine Consumption Preference. J Neurosci, 45(27) PubMed ID: 40456609
Summary: Cocaine is an addictive psychostimulant, and the risk of developing cocaine use disorder (CUD) is highly heritable. Little is known about the specific genes and mechanisms that lead to the development of CUD, and there are currently no FDA-approved pharmacotherapies that can treat it. Drosophila has proven an effective model organism to identify genes and mechanisms underlying addiction, especially alcohol use disorder. While flies exposed to cocaine display features of acute intoxication like those observed in mammals, including hyperactivity and reduced sleep, to date, there is no model of preferential cocaine self-administration in flies. This study assayed cocaine consumption in Drosophila males, as well as preference in a two-choice paradigm. Mechanisms were investigated involved in cocaine taste sensing using genetic and imaging tools. Cocaine is shown to be innately aversive to flies and that this avoidance depends on bitter sensing. Gustatory sensory neurons expressing the Gr66a bitter receptor are activated upon exposure to cocaine. Silencing of these bitter-sensing neurons or mutation of Gr66a reduces cocaine avoidance. In a longitudinal choice assay, these flies develop preference for cocaine-containing solutions within 12-18 h, whereas control flies do not. These findings show that bitter sensation protects flies from developing cocaine self-administration preference. Conversely, silencing bitter perception enables use of Drosophila as a model for experience-dependent cocaine self-administration preference. This opens the door to testing human variants associated with CUD for their causative role in cocaine self-administration in this highly tractable model organism. |
| Macartney, E. L., Burke, S., Pottier, P., Hamoudi, Z., Hart, C., Ahmed, R., Lin, Y. Q., Neely, G. G., Drobniak, S. M., Nakagawa, S. (2025). Sex-Specific Effects of Social Environment on Behaviour and Their Correlations in Drosophila melanogaster. Ecol Evol, 15(4):e71261 PubMed ID: 40290389
Summary: Environmental and individual experiences can result in immediate and persistent changes in behaviour. Often, such effects are also sex-dependent. Intraspecific interactions can be one of the most important environments an individual faces. Such social interactions are expected to affect a suite of behavioural traits and their correlations. This study used Drosophila melanogaster and high-throughput automated behavioural phenotyping to determine how social environment (group mixed sex, group single sex, and social isolation) and sex interact to affect basic behaviours (exploration, movement within a y-maze, and habituation to a startle) that likely underlie more complex behaviours such as mate searching and foraging. Such behaviours and some behavioural correlations were shown to be context- and sex-dependent. Males tended to show greater exploration, while females were more likely to show a habituation response to startle. Males and females from the mixed sex and isolated treatments showed opposite exploratory behaviour in the Y-maze, and social treatment interacted with sex to affect the rate of habituation to a startle. Females also tended to have slightly stronger trait correlations compared to males. These results show that social environment and sex can play a significant role in shaping behaviour in Drosophila melanogaster. This study provides insights into how the type of social stimulation and sex can interact to affect behaviours that are important in forming critical behaviours related to foraging and mate searching. | Wu, Z., Wu, X., Wang, Z., Ye, X., Pang, L., Wang, Y., Zhou, Y., Chen, T., Zhou, S., Wang, Z., Sheng, Y., Zhang, Q., Chen, J., Tang, P., Shen, X., Huang, J., Drezen, J. M., Strand, M. R., Chen, X. (2025). A symbiotic gene stimulates aggressive behavior favoring the survival of parasitized caterpillars. Proc Natl Acad Sci U S A, 122(18):e2422935122 PubMed ID: 40294273
Summary: Animals often exhibit increased aggression in response to starvation, while parasites often manipulate host behavior. In contrast, underlying molecular mechanisms for these behavioral changes are mostly unknown. The diamondback moth, Plutella xylostella, is an agricultural pest that feeds on cruciferous plants as larvae, while Cotesia vestalis is a parasitoid wasp that parasitizes diamondback moth larvae. In this study, we determined that unparasitized diamondback moth larvae exhibit increased aggression and cannibalism when starved, while starved larvae parasitized by C. vestalis were more aggressive than unparasitized larvae. C. vestalis harbors a domesticated endogenized virus named Cotesia vestalis bracovirus (CvBV) that wasps inject into parasitized hosts. Starvation increased octopamine (OA) levels in the central nervous system (CNS) of diamondback moth larvae while a series of experiments identified a CvBV-encoded gene product named Assailant that further increased aggression in starved diamondback moth larvae. We determined that Assailant increases OA levels by activating tyramine beta-hydroxylase (PxTβh), which is a key enzyme in the OA biosynthesis pathway. Ectopic expression of assailant in Drosophila melanogaster likewise upregulated expression of DmTβh and OA, which increased aggressive behavior in male flies as measured by a well-established assay. While parasitized hosts are often thought to be at a competitive disadvantage to nonparasitized individuals, these results uncover how a parasitoid uses an endogenized virus to increase host aggression and enhance survival of offspring when competing against unparasitized hosts. |
| Vaxenburg, R., Siwanowicz, I., Merel, J., Robie, A. A., Morrow, C., Novati, G., Stefanidi, Z., Both, G. J., Card, G. M., Reiser, M. B., Botvinick, M. M., Branson, K. M., Tassa, Y., Turaga, S. C. (2025). Whole-body physics simulation of fruit fly locomotion. Nature, PubMed ID: 40267984
Summary: The body of an animal influences how its nervous system generates behaviour. Accurately modelling the neural control of sensorimotor behaviour requires an anatomically detailed biomechanical representation of the body. This study introduces a whole-body model of the fruit fly Drosophila melanogaster in a physics simulator. Designed as a general-purpose framework, this model enables the simulation of diverse fly behaviours, including both terrestrial and aerial locomotion. Its versatility was validated by replicating realistic walking and flight behaviours. To support these behaviours, phenomenological models were developfor fluid and adhesion forces. Using data-driven, end-to-end reinforcement learning, neural network controllers capable of generating naturalistic locomotion were train along complex trajectories in response to high-level steering commands. Furthermore, this study showed the use of visual sensors and hierarchical motor control, training a high-level controller to reuse a pretrained low-level flight controller to perform visually guided flight tasks. This model serves as an open-source platform for studying the neural control of sensorimotor behaviour in an embodied context. | Yoshino, J., Mali, S. S., Williams, C. R., Morita, T., Emerson, C. E., Arp, C. J., Miller, S. E., Yin, C., The, L., Hemmi, C., Motoyoshi, M., Ishii, K., Emoto, K., Bautista, D. M., Parrish, J. Z. (2025). Drosophila epidermal cells are intrinsically mechanosensitive and modulate nociceptive behavioral outputs. Elife, 13 PubMed ID: 40353351
Summary: Somatosensory neurons (SSNs) that detect and transduce mechanical, thermal, and chemical stimuli densely innervate an animal's skin. However, although epidermal cells provide the first point of contact for sensory stimuli, understanding of roles that epidermal cells play in SSN function, particularly nociception, remains limited. This study show that stimulating Drosophila epidermal cells elicits activation of SSNs including nociceptors and triggers a variety of behavior outputs, including avoidance and escape. Further, this study found that epidermal cells are intrinsically mechanosensitive and that epidermal mechanically evoked calcium responses require the store-operated calcium channel Orai. Epidermal cell stimulation augments larval responses to acute nociceptive stimuli and promotes prolonged hypersensitivity to subsequent mechanical stimuli. Hence, epidermal cells are key determinants of nociceptive sensitivity and sensitization, acting as primary sensors of noxious stimuli that tune nociceptor output and drive protective behaviors. |
Monday, January 12th - Adult Physiology and Meteabolism |
| Wang, C., Shen, J. (2025). From metabolism to lifespan trade-offs: polyethylene microplastics induce circadian disruption and sex-specific aging in Drosophila melanogaster. Comp Biochem Physiol C Toxicol Pharmacol, 295:110214 PubMed ID: 40300706
Summary: Microplastics (MPs), particularly polyethylene microplastics (PE-MPs), are increasingly recognized as contaminants in both aquatic and terrestrial environments. However, the ecological impacts of PE-MPs on terrestrial organisms remain underexplored. This study investigates the physiological and behavioral effects of PE-MPs exposure in Drosophila melanogaster, shedding light on the potential risks posed by PE-MPs in land-based ecosystems. After exposing the fruit flies to different concentrations of PE-MPs for 20 days, several physiological biomarkers were assessed, including spontaneous behavioral activity, starvation resistance, metabolic biomarkers, and lifespan. The findings indicate that PE-MPs exposure significantly affects fruit fly physiology, with increased spontaneous activity, decreased starvation resistance, and reduced triglyceride (TG) and protein levels (in males), reflecting disruption of metabolic processes. While PE-MPs did not affect female reproductive capacity, they did result in sex-specific impacts on lifespan, with male fruit flies showing a significant reduction in both mean and median lifespan at higher PE-MPs concentrations. These results highlight the need to consider the sex-dependent nature of PE-MPs toxicity when assessing their ecological risks. This study contributes new insights into the potential for PE-MPs to disrupt terrestrial ecosystems and underscores the importance of investigating the effects of microplastics on terrestrial invertebrates, providing a foundation for future ecotoxicological research. | Rossano, A. J., Zhang, L., Anderson, J. B., Holmes, H. L., Mandal, A. K., Decker, J. W., Mount, D. B., Romero, M. F. (2025). Ex vivo quantification of intracellular pH in Drosophila Malpighian tubule reveals basolateral HCO(3) (-)/oxalate exchange through a novel oxalate transporter "Neat". Front Physiol, 16:1468451 PubMed ID: 40356774
Summary: Nephrolithiasis is a painful and costly healthcare complication. The most common kidney stones are composed of calcium oxalate and thus renal handling of oxalate is an important facet of understanding the pathogenesis of nephrolithiasis. Recently, the Drosophila melanogaster Malpighian tubule (MT) has emerged as a robust model of trans-epithelial ion transport and nephrolithiasis as MTs readily form luminal calcium-oxalate crystals in the presence of oxalate. Drosophila Prestin (dPrestin, Slc26a6) transports oxalate across the apical surface of the MT into the lumen. The objective of this work was to identify and characterize the Drosophila basolateral Ox(2-) transporter through ex vivo real-time quantification of intracellular pH (pH(i)). A putative basolateral oxalate transporter "CG5002 ("Neat") was identified through sequence homology and displayed robust Cl(-)-independent Ox(2-) transport and electroneutral Ox(2-) transport in Xenopus oocytes. pH(i) in extracted fly MTs was monitored. Basolateral perfusion of MTs in CO(2)/HCO(3) (-)-buffered solution produced a large acidification followed by rapid recovery in the transitional segment of the anterior MT. Recovery was interrupted by basolateral application of 1 mM Ox(2-) or 1 mM SO(4). Tissue specific knock-down of Neat with interference RNA (RNAi) reduced the rate of acid-loading in the transitional segment of the MT with regard to Ox(2-) and SO(4). Knockdown of Neat in the MT also significantly reduced luminal calcium oxalate crystal formation in a fly ex vivo model of calcium oxalate nephrolithiasis. These data indicate Neat is a significant Drosophila basolateral MT oxalate transporter and the basolateral movement of oxalate is functionally coupled to movement of acid equivalents, potentially as Ox(2-)/HCO(3) (-) exchange, Ox(2-)/OH(-) exchange, or Ox(2-):H(+) co-transport. |
| Rai, M., Li, H., Policastro, R. A., Pepin, R., Zentner, G. E., Nemkov, T., D'Alessandro, A., Tennessen, J. M. (2025). Glycolytic disruption restricts Drosophila melanogaster larval growth via the cytokine Upd3. PLoS Genet, 21(5):e1011690 PubMed ID: 40315265
Summary: Drosophila larval growth requires efficient conversion of dietary nutrients into biomass. Lactate dehydrogenase (Ldh) and glycerol-3-phosphate dehydrogenase (Gpdh1) support this larval metabolic program by cooperatively promoting glycolytic flux. Consistent with their cooperative functions, the loss of both enzymes, but not either single enzyme alone, induces a developmental arrest. However, Ldh and Gpdh1 exhibit complex and often mutually exclusive expression patterns, suggesting that the lethal phenotypes exhibited by Gpdh1; Ldh double mutants could be mediated non-autonomously. Supporting this possibility, the developmental arrest displayed by double mutants was found to extends beyond simple metabolic disruption and instead stems, in part, from changes in systemic growth factor signaling. Specifically, it was demonstrated that the simultaneous loss of Gpdh1 and Ldh results in elevated expression of Upd3, a cytokine involved in Jak/Stat signaling. Furthermore, upd3 loss-of-function mutations was shown to suppress the Gpdh1; Ldh larval arrest phenotype, indicating that Upd3 signaling restricts larval development in response to decreased glycolytic flux. Together, these findings reveal a mechanism by which metabolic disruptions can modulate systemic growth factor signaling. | Van De Poll, M. N., van Swinderen, B. (2025). Long-term multichannel recordings in Drosophila flies reveal altered predictive processing during sleep compared with wake. J Exp Biol, 228(11) PubMed ID: 40296777
Summary: During sleep, behavioral responsiveness to external stimuli is decreased. This classical definition of sleep has been applied effectively across the animal kingdom to identify this common behavioral state in a growing list of creatures, from mammals to invertebrates. Yet, it remains unclear whether decreased behavioral responsiveness during sleep is necessarily associated with decreased responsiveness in brain activity, especially in insects. Long-term multichannel electrophysiology was performed in tethered Drosophila melanogaster flies exposed continuously to repetitive visual stimuli. Flies were still able to sleep under these visual stimulation conditions, as determined by traditional immobility duration criteria for the field. Interestingly, this study did not find any difference between responses to repetitive visual stimuli during sleep compared with wake when we recorded local field potentials (LFPs) across a transect of the fly brain from optic lobes to the central brain. However, LFP responses were found to be altered when visual stimuli were variable and of lower probability, especially in the central brain. Central brain responses to less predictable or 'deviant' stimuli were lower during the deepest stage of sleep, a time of quiescence characterized by more regular proboscis extensions. This shows that the sleeping fly brain processes low-probability visual stimuli in a different way from more repeated stimuli, and presents Drosophila as a promising model for studying the potential role of sleep in regulating predictive processing. |
| Yu, G., Yang, Q., Wu, Q. (2025). Rapamycin Alters the Feeding Preference for Amino Acids and Sugar in Female Drosophila. J Gerontol A Biol Sci Med Sci, 80(7) PubMed ID: 40296844
Summary: Rapamycin has demonstrated significant lifespan-extending effects across a variety of model organisms, positioning it as one of the most promising antiaging agents currently under investigation. Nonetheless, chronic administration of rapamycin may induce diverse adverse reactions, primarily due to its influence on energy metabolism. Using Drosophila melanogaster as a model, this study showed that rapamycin significantly alters feeding behaviors in a dose-dependent manner. Specifically, both long-term and short-term administration of the optimal life-extending dose of rapamycin decreases the protein preference while increasing sugar intake in female flies. Utilizing a chemically defined diet, these alterations in amino acid and sugar feeding preferences were shown to occur as early as the second day of rapamycin exposure, preceding any detectable decline in fecundity. Furthermore, rapamycin also modifies amino acid preference even in taste-blind females, indicating that postingestive nutritional learning mechanisms, independent of food taste value, are sufficient to mediate the effects of rapamycin on feeding behavior. However, such changes in macronutrient preferences were absent in males and sterile mutant females. Collectively, this study suggests that the modification of feeding behavior could be a non-negligible side effect of rapamycin treatment, and this effect is influenced by both sex and reproductive status. | Subaric, D., Rastija, V., Karnas Babi , M., Agic, D., Majic, I. (2025). Structural Features of Coumarin-1,2,4-Triazole Hybrids Important for Insecticidal Effects Against Drosophila melanogaster and Orius laevigatus (Fieber). Molecules, 30(8) PubMed ID: 40333563
Summary: Although the present use of pesticides in plant protection has limited the occurrence and development of plant diseases and pests, resistance to pesticides and their environmental and health hazards indicates an urgent need for new active ingredients in plant protection products. Recently synthesized coumarin-1,2,4-triazole hybrid compounds have been proven effective against plant pathogenic fungi and safe for soil-beneficial bacteria. Drosophila melanogaster, the common fruit fly, has been used as a model organism for scientific research. Additionally, it is considered a pest since it damages fruits and serves as a carrier for various plant diseases. On the contrary, Orius laevigatus is a beneficial true bug that biologically controls harmful arthropods in agricultural production. In the present study, an adulticidal bioassay was performed against D. melanogaster and O. laevigatus using coumarin-1,2,4-triazole hybrids. Quantitative structure-activity relationship studies (QSARs) and in silico ecotoxicity evaluation elucidated the structural features underlying the compounds' insecticidal activity. The derivative of 4-methylcoumarin-1,2,4-triazole with a 3-bromophenyl group showed great insecticidal potential. A molecular docking study indicated that the most active compound probably binds to glutamate-gated chloride channels. |
Thursday, January 8th - Disease models |
| Ti, X., Zuo, H., Zhao, G., Li, Y., Du, M., Xu, L., Li, S., Shan, Z., Gao, Y., Gan, G., Wang, Y., Zhang, Q. (2025). Parkin mediates the mitochondrial dysfunction through mRpL18. J Biol Chem, 301(6):110208 PubMed ID: 40345588
Summary: Loss of function of parkin leads to mitochondrial dysfunction, which is closely related to Parkinson's disease. However, the in vivo mechanism is far from clear. One dogma is that impaired Parkin causes dysfunction of mitophagy mediated by Pink1-Parkin axis. The other is that impaired Parkin causes Mfn accumulation which leads to mitochondrial dysfunction. Surprisingly, in Drosophila muscles, the first dogma is not applicable; for the second dogma, this study suggests that Parkin mediates mitochondrial dysfunction through the synergy of both Marf and mitochondrial protein mRpL18 got from a genome-wide screen, whose RNAi rescues parkin RNAi phenotype. Mechanistically, this study found that impaired Parkin upregulated both transcription and protein levels of mRpL18 dependent on its E3 ligase activity, causing mRpL18 accumulation outside mitochondria. Consequently, cytosolic-accumulated mRpL18 competitively bound Drp1, leading to the reduction of the binding of Drp1 to its receptor Fis1, which finally inhibited mitochondrial fission and tipped the balance to mitochondrial hyperfusion, thereby affected the mitochondrial function. Taken together, our study suggests that impaired Parkin causes mitochondrial hyperfusion due to two reasons: (1) Parkin defect impairs Pink1-Parkin axis-mediated Marf degradation, which promotes mitochondrial fusion; (2) Parkin defect causes mRpL18 accumulation, which inhibits Drp1/Fis1-mediated mitochondrial fission. These two ways together drive Parkin-mediated mitochondrial hyperfusion. Therefore, knockdown of either marf or mRpL18 can prevent mitochondrial hyperfusion, leading to the rescue of Parkin defect-triggered fly wing phenotypes. Overall, this study unveils a new facet of how Parkin regulates mitochondrial morphology, which provides new insights for the understanding and treatment of Parkinson's disease. | Scudese, E., Marshall, A. G., Vue, Z., Exil, V., ..., Sharma, V., Mobley, B. C., Katti, P., Hinton, A. (2025). 3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights Into MFN-2-Mediated Changes. Aging Cell:e70054 PubMed ID: 40285369
Summary: Age-related skeletal muscle atrophy, known as sarcopenia, is characterized by loss of muscle mass, strength, endurance, and oxidative capacity. Although exercise has been shown to mitigate sarcopenia, the underlying governing mechanisms are poorly understood. Mitochondrial dysfunction is implicated in aging and sarcopenia; however, few studies explore how mitochondrial structure contributes to this dysfunction. This study sought to understand how aging impacts mitochondrial three-dimensional (3D) structure and its regulators in skeletal muscle. We hypothesized that aging leads to remodeling of mitochondrial 3D architecture permissive to dysfunction and is ameliorated by exercise. Using serial block-face scanning electron microscopy (SBF-SEM) and Amira software, mitochondrial 3D reconstructions from patient biopsies were generated and analyzed. Across five human cohorts, differences in magnetic resonance imaging, mitochondria 3D structure, exercise parameters, and plasma immune markers were correlate between young (under 50 years) and old (over 50 years) individuals. Mitochondria are less spherical and more complex, indicating age-related declines in contact site capacity. Additionally, aged samples showed a larger volume phenotype in both female and male humans, indicating potential mitochondrial swelling. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age-related losses. Exercise stimulation restored mitofusin 2 (MFN2), one such of these mitochondrial dynamic proteins, which this study showed is required for the integrity of mitochondrial structure. Furthermore, this pathway is evolutionarily conserved, as Marf, the MFN2 ortholog in Drosophila, knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. These results define age-related structural changes in mitochondria and further suggest that exercise may mitigate age-related structural decline through modulation of mitofusin 2. |
| Tan, S. L., Neumann, D., Trim, P. J., Hewson, L. J., Mustaffar, N. F., He, Q. Q., Wimmer, N., Snel, M. F., Ferro, V., O'Keefe, L. V., Hemsley, K. M., Lau, A. A. (2025). Substrate reduction using a glucosamine analogue in Drosophila melanogaster and mouse models of Sanfilippo syndrome. Mol Genet Metab, 145(2):109112 PubMed ID: 40288156
Summary: Mucopolysaccharidosis (MPS) types III A and C are inherited neurodegenerative disorders resulting from the lack of a specific enzyme involved in heparan sulfate (HS) catabolism, leading to the accumulation of partially-degraded HS fragments. At present, there are no approved treatments and death is commonly in the second decade of life. Several therapies have undergone pre-clinical evaluation for these conditions, including substrate reduction therapy, with the most studied compound of this class being the isoflavone genistein. However, findings from a Phase III clinical trial demonstrated that high dose oral genistein did not significantly improve neurodevelopmental outcomes in patients with MPS III (Sanfilippo syndrome). This study tested an N-acetylglucosamine analogue, 4-deoxy-N-acetylglucosamine peracetate, as a novel substrate reduction therapy for HS-storing lysosomal storage disorders such as MPS III. Treatment with this compound significantly reduced HS levels in cultured MPS IIIA patient and mouse fibroblasts in a time- and dose-dependent manner. MPS IIIC Drosophila fed 4-deoxy-N-acetylglucosamine peracetate contained significantly less HS relative to those raised on control diets. Likewise, improvements in HS load within the MPS IIIA mouse brain suggests that the compound crossed the blood-brain barrier after oral administration. Although long-term studies are needed, these findings indicate that 4-deoxy-GlcNAc peracetate may be beneficial in slowing the accumulation of HS and may represent a novel substrate reduction therapeutic for MPS III and potentially other HS-storing disorders. | Singh, K., Gupta, K., Shukla, S., Kumari, A. P., Kumar, A. (2025). Repurposing Oseltamivir Against CAG Repeat Mediated Toxicity in Huntington's Disease and Spinocerebellar Ataxia Using Cellular and Drosophila Model. ACS Omega, 10(15):14980-14993 PubMed ID: 40290909
Summary: Huntington's disease (HD) and Spinocerebellar Ataxia (SCA) are debilitating neurological disorders triggered by the expansion of CAG sequences within the specific genes (HTT and ATXN, respectively). These are characterized as poly glutamine (polyQ) disorders, which are marked by widespread neurodegeneration and metabolic irregularities across systemic, cellular, and intracellular levels. This study aimed to identify small molecules that specifically interact with and target the toxic CAG repeat RNA. This study investigated the neuroprotective effects of Oseltamivir, an antiviral drug, against the HD and SCA-causing CAG repeats, through biophysical, cellular, and Drosophila model-based studies. Using a multidimensional approach encompassing biophysical techniques, cellular assays, and a Drosophila model, Oseltamivir's interaction with toxic CAG repeat RNA was explored. These comprehensive analyses, including circular dichroism (CD), isothermal titration calorimetry (ITC), electrophoretic mobility shift assay (EMSA), and nuclear magnetic resonance (NMR) spectroscopy, demonstrated Oseltamivir's specific binding affinity for AA mismatches and its potential to mitigate the toxicity associated with polyQ aggregation. Moreover, the identified U.S. FDA-approved drug effectively mitigated polyQ-induced toxicity in both HD cells and the Drosophila model of the disease. The results obtained from this drug repurposing approach are indicative of the neuro-shielding role of Oseltamivir in HD and several SCAs, paving the way for its translation into clinical practice to benefit patients afflicted with these devastating diseases. |
| Song, H., Kim, S., Han, J. E., Kang, K. H., Koh, H. (2025). PDH Inhibition in Drosophila Ameliorates Sensory Dysfunction Induced by Vincristine Treatment in the Chemotherapy-Induced Peripheral Neuropathy Models. Biomedicines, 13(4) PubMed ID: 40299339
Summary: Chemotherapy-induced peripheral neuropathy (CIPN) is a significant dose-limiting side effect of many effective anticancer agents, including vincristine. While CIPN adversely affects both oncological outcomes and the quality of life for cancer patients, the in vivo mechanisms behind CIPN pathology remain largely unknown, and effective treatments have yet to be developed. This study established a novel Drosophila model of CIPN using vincristine to explore the molecular mechanisms underlying this condition. The impact of vincristine exposure on thermal nociception in Drosophila larvae was assessed using a programmable heat probe. Additionally, vincristine-induced mitochondrial dysfunction and dendritic abnormalities in class IV dendritic arborization (C4da) neurons was investigated with various fluorescent protein markers. A dose-dependent increase in thermal hypersensitivity was found, accompanied by changes in the sensory dendrites of C4da neurons in vincristine-treated fly larvae. Moreover, vincristine significantly enhanced mitochondrial ROS production and mitophagy-a selective autophagy that targets dysfunctional mitochondria-indicating vincristine-induced mitochondrial dysfunction within C4da neurons. Surprisingly, inhibiting the pyruvate dehydrogenase complex (PDH), a key mitochondrial metabolic enzyme complex, effectively rescued the mitochondrial and sensory abnormalities caused by vincristine.Findings from this first Drosophila model of vincristine-induced peripheral neuropathy (VIPN) suggest that mitochondrial dysfunction plays a critical role in VIPN pathology, representing PDH as a potential target for the treatment of VIPN. | Serebryany-Piavsky, V., Egulsky, L., Manoim-Wolkovitz, J. E., Anis, S., Hassin-Baer, S., Parnas, M., Horowitz, M. (2025). The modifying effect of mutant LRRK2 on mutant GBA1-associated Parkinson disease. Hum Mol Genet, 34(14):1184-1203 PubMed ID: 40315377
Summary: Parkinson disease (PD) is the second most common neurodegenerative disease. While most cases are sporadic, in ~5%-10% of PD patients the disease is caused by mutations in several genes, among them GBA1 (glucocerebrosidase beta 1) and LRRK2 (leucine-rich repeat kinase 2), both prevalent among the Ashkenazi Jewish population. LRRK2-associated PD tends to be milder than GBA1-associated PD. Several recent clinical studies have suggested that carriers of both GBA1 and LRRK2 mutations develop milder PD compared to that observed among GBA1 carriers. These findings strongly suggested an interplay between the two genes in the development and progression of PD. In the present study Drosophila was employed as a model to investigate the impact of mutations in the LRRK2 gene on mutant GBA1-associated PD. The results strongly indicated that flies expressing both mutant genes exhibited milder parkinsonian signs compared to the disease developed in flies expressing only a GBA1 mutation. This was corroborated by a decrease in the ER stress response, increase in the number of dopaminergic cells, elevated levels of tyrosine hydroxylase, reduced neuroinflammation, improved locomotion and extended survival. Furthermore, a significant decrease in the steady-state levels of mutant GBA1-encoded GCase was observed in the presence of mutant LRRK2, strongly implying a role for mutant LRRK2 in degradation of mutant GCase. |
Monday, January 5th - Larval and Adult Development |
| Lee, U., Li, C., Langer, C. B., Svetec, N., Zhao, L. (2025). Comparative single-cell analysis of transcriptional bursting reveals the role of genome organization in de novo transcript origination. Proc Natl Acad Sci U S A, 122(18):e2425618122 PubMed ID: 40305051
Summary: Spermatogenesis is a key developmental process underlying the origination of newly evolved genes. However, rapid cell type-specific transcriptomic divergence of the Drosophila germline has posed a significant technical barrier for comparative single-cell RNA-sequencing studies. By quantifying a surprisingly strong correlation between species- and cell type-specific divergence in three closely related Drosophila species, a statistical procedure was applied to identify a core set of 198 genes that are highly predictive of cell type identity while remaining robust to species-specific differences that span over 25 to 30 My of evolution. Then cell type classifications based on the 198-gene set were used to show how transcriptional. divergence in cell type increases throughout spermatogenic developmental time. After validating these cross-species cell type classifications using RNA fluorescence in situ hybridization and imaging, this study then investigated the influence of genome organization on the molecular evolution of spermatogenesis vis-a-vis transcriptional bursting. Altering transcriptional burst size was shown to contribute to premeiotic transcription and altering bursting frequency contributes to postmeiotic expression. Global differences in autosomal vs. X chromosomal transcription may arise in a developmental stage preceding full testis organogenesis were illustrated by showing evolutionarily conserved decreases in X-linked transcription bursting kinetics in all examined somatic and germline cell types. Finally, evidence is provided supporting the cultivator model of de novo gene origination by demonstrating how the appearance of newly evolved testis-specific transcripts potentially provides short-range regulation of neighboring genes' transcriptional bursting properties during key stages of spermatogenesis. | Wang, L., Bu, T., Gao, S., Yun, D., Chen, H., Cheng, C. Y., Sun, F. (2025). PCP protein Prickle 1 regulates Sertoli cell and testis function via cytoskeletal organization through the recruitment of multiple regulatory proteins. Am J Physiol Cell Physiol, 328(6):C2032-c2056 PubMed ID: 40327382
Summary: Prickle 1, an ortholog found in Drosophila, was localized at the Sertoli cell-spermatid interface consistent with its role of supporting the Vangl2 planar cell polarity (PCP), which is an integral membrane protein that creates the PCP protein complex of Vangl2 (Van Gogh-like 2)/Prickle1. Together with the asymmetrically localized transmembrane protein Frizzled (Fzd) and its unique adaptor proteins Disheveled (Dvl) and Inversin (Inv), Vangl2/Prickle1 and Fzd/Dvl/Inv are the two heterodimeric interacting PCP proteins between Sertoli cells and condensed spermatids to confer spermatid PCP across the plane of the seminiferous epithelium. The initial intention of this work was to examine if the distribution and expression of Prickle1 using a primary Sertoli cell in vitro model and Sprague-Dawley rats in vivo would mimic much of the earlier reported findings of Vangl2. Unexpectedly, these findings indicated that Prickle1 supported the PCP protein Vangl2; however, Prickle1 is also a multifunctional protein. First, Prickle1 knockdown (KD) by RNAi impeded Sertoli cell TJ function by perturbing the distribution of the BTB-associated proteins at the cell-cell interface, through disruption of the microtubule (MT) and actin cytoskeletal organization including their respective polymerization (and/or bundling) capability. Second, these findings were reproduced using an in vivo model of RNAi by KD of Prickle 1 in the testis. Third, using coimmunoprecipitation (Co-IP), Prickle 1 was found to interact with a host of adaptor proteins crucial to support not only PCP, such as Dvl, but also regulatory cytoskeletal proteins of MT and actin networks, including RhoA, Arp3, Cdc42, ZO-1, and β-catenin by immunoprecipitation-mass spectrometry (IP-MS) using the String Protein Interaction Tool. |
| Ku, H. Y., Bilder, D. (2025). Basement membrane patterning by spatial deployment of a secretion-regulating protease. Proc Natl Acad Sci U S A, 122(20):e2412161122 PubMed ID: 40359035
Summary: While paradigms for patterning of cell fates in development are well established, paradigms for patterning morphogenesis, particularly when organ shape is influenced by the extracellular matrix (ECM), are not. Morphogenesis of the Drosophila egg chamber (follicle) depends on anterior-posterior distribution of basement membrane (BM) components such as Collagen IV (Col4), whose gradient creates tissue mechanical properties that specify the degree of elongation. This study shows that the gradient is not regulated by Col4 transcription but instead relies on posttranscriptional mechanisms. The metalloprotease ADAMTS-A, expressed in a gradient inverse to that of Col4, limits Col4 deposition in the follicle center and manipulation of its levels can cause either organ hyper- or hypoelongation. Evidence is presented that ADAMTS-A acts within the secretory pathway, rather than extracellularly, to limit Col4 incorporation into the BM. High levels of ADAMTS-A in follicle termini are normally dispensable but suppress Col4 incorporation when transcription is elevated. Meanwhile, the terminally expressed metalloprotease Stall increases Col4 turnover in the posterior. These data show how an organ can employ patterned expression of ECM proteases with intracellular as well as extracellular activity to specify BM properties that control shape. | Simmons, C., Williams, I. H., Bradshaw, T. W., Armstrong, A. R. (2025). Adipocyte-Derived CCHamide-1, Eiger, Growth-Blocking Peptide 3, and Unpaired 2 Regulate Drosophila melanogaster Oogenesis. Biomolecules, 15(4) PubMed ID: 40305230
Summary: In addition to energy storage, adipose tissue communication to other organs plays a key role in regulating organismal physiology. While the link between adipose tissue dysfunction and pathophysiology, including diabetes, chronic inflammation, and infertility, is clear, the molecular mechanisms that underlie these associations have not been fully described. This study used Drosophila melanogaster as a model to better understand how adipose tissue communicates to the ovary. This study utilized D. melanogaster's robust genetic toolkit to examine the role of five adipokines known to control larval growth during development, CCHamide-1, CCHamide-2, eiger, Growth-blocking peptide 3, and unpaired 2 in regulating oogenesis. The adult fat body expresses these "larval" adipokines. The data indicate that ovarian germline stem cell maintenance does not require these adipokines. However, adipocyte-derived CCHamide-1, eiger, Growth-blocking peptide 3, and unpaired 2 influence early and late germline survival as well as ovulation. Thus, this work uncovers several adipokines that mediate fat-to-ovary communication. |
| Peng, J., Sun, A., Zheng, J., Zhang, N., Zhang, X., Gao, G. (2025). Testis-specific serine/threonine kinase dTSSK2 regulates sperm motility and male fertility in Drosophila. Commun Biol, 8(1):710 PubMed ID: 40335644
Summary: Serine/threonine kinases of the TSSK (Testis-Specific Serine/Threonine Kinase) family play crucial roles in spermatogenesis and male fertility across species, but the underlying regulatory mechanism remains incompletely understood. In this study, we identified and characterized a novel TSSK homolog in Drosophila, named dTSSK2 (CG9222), which functions as the ortholog of human TSSK4. dTSSK2 is specifically expressed in the testis and localizes to individualization complexes during spermiogenesis. Disruption of dTSSK2 severely compromises sperm motility, leading to failed sperm transit into the seminal vesicle and male infertility. Phosphoproteomic analyses reveal that dTSSK2 coordinates sperm flagella assembly and motility by phosphorylating proteins involved in microtubule organization, organelle assembly, and flagella structure. Notably, dTSSK2 phosphorylates the substrate Gudu at Ser9, which partially contributes to individualization complex integrity and sperm motility. These findings elucidate the critical role of dTSSK2-mediated phosphorylation in regulating Drosophila male fertility. | Otsune, S., Matsuka, M., Shirakashi, C., Zhang, X., Nakagoshi, H. (2025). Polished Rice Regulates Maturation but Not Survival of Secondary Cells in Drosophila Male Accessory Gland. Genes Cells, 30(3):e70025 PubMed ID: 40346918
Summary: In Drosophila males, the accessory gland is responsive to nutrient signal-dependent regulation of fertility/fecundity. The accessory gland is composed of two types of binucleated epithelial cells, about 1000 main cells and 60 secondary cells (SCs). The transcription factors Defective proventriculus (Dve), XF../segment/abdomlb1.htm">Abdominal-B, and Ecdysone receptors (EcRs) are strongly expressed in adult SCs. In response to nutrient conditions during development, coordinated action between Dve and ecdysone signaling determines the optimal number of SCs and regulates their maturation. A downstream effector of ecdysone signaling, Ftz-F1, is crucial in this process. Another downstream effector, Polished rice (Pri), is small peptides of 11 or 32 amino acids. This study shows that pri is required for maturation of SCs and for male fecundity, whereas it is not involved in determination of the number of SCs. Evidence is provided that Pri acts downstream of Ftz-F1 to regulate maturation but not survival of SCs. |
Monday,January 5th - Larval and Adult Development |
| Harsh, S., Liu, H. Y., Bhaskar, P. K., Rushlow, C., Bach, E. A. (2025). Post-transcriptional suppression of the pioneer factor Zelda protects the adult Drosophila testis from activation of the ovary program. PLoS Biol, 23(12):e3003535 PubMed ID: 41411219
Summary: Maintenance of somatic sex identity is essential for adult tissue function. In the Drosophila testis, adult somatic stem cells known as cyst stem cells (CySCs) require the transcription factor Chinmo to preserve male identity. Loss of Chinmo leads to reprogramming of CySCs into their ovarian counterparts through induction of the female-specific RNA-binding protein TransformerF (TraF), though the underlying mechanism has remained unclear. This study identified the pioneer transcription factor Zelda (Zld) as a critical mediator of this sex reversal. In wild-type CySCs, zld mRNA is repressed by microRNAs (miRs), but following Chinmo loss, these miRs are downregulated, allowing zld mRNA to be translated. Zld is necessary for feminization of chinmo-mutant CySCs, and ectopic expression of Zld in wild-type CySCs is sufficient to induce TraF and drive female reprogramming. Two Zld target genes, qkr58E-2 and Ecdysone receptor (EcR), are upregulated in chinmo-mutant CySCs and are normally female-biased in adult gonads. Qkr58E-2 facilitates TraF production, while EcR promotes female gene expression programs. Zld overexpression feminizes otherwise wild-type CySCs by upregulating EcR, which in turn downregulates the chinmo gene. Strikingly, overexpression of Zld also feminizes adult male adipose tissue by inducing TraF and downregulating Chinmo, indicating that Zld can override male identity in multiple adult XY tissues. Together, these findings uncover a post-transcriptional mechanism in which miRs-mediated repression of a pioneer factor safeguards male identity and prevents inappropriate activation of the female program in adult somatic cells. | Song, Y., Martin, P., Sun, T., Fernandez-Herrero, J., Sanchez-Herrero, E., Pastor-Pareja, J. C. (2025). Mechanical coupling between dorsal and ventral surfaces shapes the Drosophila haltere. Curr Biol, 35(13):3090-3105.e3095 PubMed ID: 40505664
Summary: The extracellular matrix is an essential determinant of animal form, enabling organization of cells and tissues into organs with complex shapes. In contrast with the dorso-ventrally flat Drosophila wing, its serial homolog, the haltere, adopts a globular shape thought to arise from a lack of matrix-mediated adhesion between its dorsal and ventral surfaces. Contradicting this model, however, matrix manipulations are known to deform halteres. To understand haltere morphogenesis, this study characterized matrix behavior and monitored metamorphic development of the haltere. Similar to the wing, correct haltere morphogenesis was found to require collagen IV degradation, which is mediated by ecdysone-controlled expression of matrix metalloprotease 2 in both wing and haltere. After collagen IV is degraded, similar again to the wing, dorsal and ventral haltere surfaces establish laminin-mediated contact through long cytoskeletal projections. Furthermore, time-lapse analysis of shape changes in wild-type and mutant halteres indicates that these projections couple the two surfaces through a central tensioner, ensuring load distribution across the whole organ to create a globular shape against tissue-wide deforming forces. These findings reveal an unexpected role for matrix-mediated adhesion in haltere morphogenesis and describe a novel type of matrix-based tensor structure building a 3D shape from 2D epithelia. |
| Bose, A., Schuster, K., Kodali, C., Sonam, S., Smith-Bolton, R. K. (2025). The pioneer transcription factor Zelda controls the exit from regeneration and restoration of patterning in Drosophila. Sci Adv, 11(23):eads5743 PubMed ID: 40479065
Summary: Many animals can regenerate tissues after injury. While the initiation of regeneration has been studied extensively, how the damage response ends and normal gene expression returns is unclear. This study found that in Drosophila wing imaginal discs, the pioneer transcription factor Zelda controls the exit from regeneration and return to normal gene expression. Optogenetic inactivation of Zelda during regeneration disrupted patterning, induced cell fate errors, and caused morphological defects yet had no effect on normal wing development. Using Cleavage Under Targets & Release Using Nuclease, targets of Zelda important for the end of regeneration were identified, including genes that control wing margin and vein specification, compartment identity, and cell adhesion. GAGA factor and Fork head similarly coordinate patterning after regeneration and that chromatin regions bound by Zelda increase in accessibility during regeneration. Thus, Zelda orchestrates the transition from regeneration to normal gene expression, highlighting a fundamental difference between developmental and regeneration patterning in the wing disc. | Choi, B. J., Chen, Y. C., Desplan, C. (2025). Retinal Calcium Waves Coordinate Uniform Tissue Patterning of the Drosophila Eye. bioRxiv, PubMed ID: 40501815
Summary: Optimal neural processing relies on precise tissue patterning across diverse cell types. This study shows that spontaneous calcium waves arise among non-neuronal support cells in the developing Drosophila eye to drive retinal morphogenesis. Waves are initiated by Cad96Ca receptor tyrosine kinase signaling, triggering PLCγ-mediated calcium release from the endoplasmic reticulum. A cell-type-specific 'Innexin-code' coordinates wave propagation through a defined gap junction network among non-neuronal retinal cells, excluding photoreceptors. Wave intensity scales with ommatidial size, triggering stronger Myosin II-driven apical contractions at interommatidial boundaries in larger ommatidia. This size-dependent mechanism compensates for early boundary irregularities, ensuring uniform ommatidial packing critical for precise optical architecture. These findings reveal how synchronized calcium signaling among non-neuronal cells orchestrates tissue patterning in the developing nervous system. |
| Walker, B. M., Palumbo, R. J., Knutson, B. A. (2025). Tissue-specific requirement of Polr1D in the prothoracic gland for ecdysone-mediated developmental transitions in Drosophila melanogaster. Dev Dyn, PubMed ID: 40317818
Summary: Polr1D is a shared subunit of RNA Polymerases I and III, which transcribe the rRNA incorporated into ribosomes. Mutations in POLR1D cause Treacher Collins syndrome, a craniofacial disorder that arises from impaired ribosome biogenesis in neural crest cells. Previous work found that RNAi knockdown of Polr1D in several non-neural Drosophila tissues caused developmental defects that phenocopy mutations affecting ecdysone signaling. Ecdysone is a steroid hormone produced in the prothoracic gland (PG) of insects that triggers developmental transitions. This study shows that Polr1D is required for PG development and ecdysone production to facilitate larval developmental transitions. Polr1D RNAi in the PG causes larval developmental arrest due to defective peripheral ecdysone signaling. Polr1D is required for the growth of PG cells and for maintaining nucleolar structure. Polr1D was also shown to be required for the synthesis of mature ribosomes and the production of the Pol III-transcribed 7SK RNA. Furthermore, developmental arrest of Polr1D RNAi larvae and Polr1D mutant (G30R) larvae was partially rescued by treatment with exogenous ecdysone. These results demonstrate a role for Drosophila Polr1D in PG development and suggest that disruptions in human Polr1D might impact additional cell types during development. | Ready, D. F., Chang, H. C. (2025). Drosophila photoreceptor tethering by a laminin-Eys scaffold. iScience, 28(6):112732 PubMed ID: 40520108
Summary: Visual acuity in Drosophila requires precise photoreceptor alignment along the optical axis, maintained by longitudinal tension between a rigid cornea and a contractile retinal base. This study identified the rhabdomere caps-an extracellular matrix (ECM) structure that links rhabdomere tips to the integrin-decorated basal surfaces of overlying, lens-forming cone cells. Rhabdomere caps form perlecan-filled peaks shaped by a trapezoidal LanB1 (laminin) grid, which mirrors the inter-rhabdomeral space (IRS) contour. This study revealed that Eys (eyes shut), a photoreceptor-secreted proteoglycan essential for IRS formation, guides LanB1 and perlecan deposition by cone cells during pupal development. Disruption of LanB1 results in rhabdomere tip detachment, IRS collapse, and impaired tension transmission. These findings reveal that cone cells and photoreceptors collaboratively sculpt a rigid LanB1 grid that caps and reinforces the distal IRS lumen. This composite ECM structure preserves rhabdomere organization and evenly distributes mechanical forces, ensuring photoreceptor alignment and optical fidelity. |
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