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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 | Yasunaga, R., Nakano, M., Kyuma, T., Fujii, K., Inui, H., Akutsu, J., Yonemura, I., Inoue, T., Suwa, A., Yoshizane, T., Nakao, A., Mori, Y. (2025). A novel insecticide cybenzoxasulfyl potently binds to vesicular acetylcholine transporter and disrupts the storage and release of acetylcholine in insects. Biochem Biophys Res Commun, 763:151792 PubMed ID: 40233436
Summary: Agrochemicals play an important role in solving global food problems and achieving a safe and sustainable society by protecting crops from pests and diseases, controlling weeds, and protecting human and animal health. The evolution of insecticide-resistant pests is a serious problem worldwide, and repeated use of insecticides with the same mode of action (MoA) promotes the evolution of resistance. Therefore, the development of insecticides with novel MoAs is important for controlling pests that are resistant to existing insecticides, thereby preventing the depletion of effective insecticides. Based on genetic studies in Caenorhabditis elegans and biochemical studies in Drosophila melanogaster, this study found that a new insecticide under development, cybenzoxasulfyl, binds directly to the vesicular acetylcholine transporter (VAChT) with low nanomolar K(d) values and inhibits acetylcholine (ACh) storage in synaptic vesicles and cholinergic signaling, thereby exerting insecticidal effects. Competitive binding assays against [(3)H]-vesamicol suggested that cybenzoxasulfyl occupies the same binding site on VAChT in a different way than vesamicol, which has long been studied as a VAChT inhibitor. This study has also revealed the metabolic pathway of cybenzoxasulfyl in Spodoptera litura, an agriculturally important lepidopteran pest, and the inhibitory effects retained by its immediately downstream metabolites using pharmacokinetic analysis and binding assay. Hence, cybenzoxasulfyl represents a promising new insecticide that acts on the VAChT and is expected to provide long-lasting activity against a variety of invertebrate pests that have evolved resistance. | Richens, J. H., Dmitrieva, M., Zenner, H. L., Muschalik, N., Butler, R., Glashauser, J., Camelo, C., Luschnig, S., Munro, S., Rittscher, J., St Johnston, D. (2025). MSP-tracker: A versatile vesicle tracking software tool used to reveal the spatial control of polarized secretion in Drosophila epithelial cells. PLoS Biol, 23(4):e3003099 PubMed ID: 40208901
Summary: Understanding how specific secretory cargoes are targeted to distinct domains of the plasma membrane in epithelial cells requires analyzing the trafficking of post-Golgi vesicles to their sites of secretion. We used the RUSH (retention using selective hooks) system to synchronously release an apical cargo, Cadherin 99C (Cad99C), and a basolateral cargo, the ECM protein Nidogen, from the endoplasmic reticulum and followed their movements to the plasma membrane. An interactive vesicle tracking framework, MSP-tracker and viewer, was developed that exploits developments in computer vision and deep learning to determine vesicle trajectories in a noisy environment without the need for extensive training data. MSP-tracker outperformed other tracking software in detecting and tracking post-Golgi vesicles, revealing that Cad99c vesicles predominantly move apically with a mean speed of 1.1μm/sec. This is reduced to 0.85 μm/sec by a dominant slow dynein mutant, demonstrating that dynein transports Cad99C vesicles to the apical cortex. Furthermore, both the dynein mutant and microtubule depolymerization cause lateral Cad99C secretion. Thus, microtubule organization plays a central role in targeting apical secretion, suggesting that Drosophila does not have distinct apical versus basolateral vesicle fusion machinery. Nidogen vesicles undergo planar-polarized transport to the leading edge of follicle cells as they migrate over the ECM, whereas most Collagen is secreted at trailing edges. The follicle cells therefore bias secretion of different ECM components to opposite sides of the cell, revealing that the secretory pathway is more spatially organized than previously thought. |
| Bhupana, J. N., Pabon, A., Leung, H. H., Rajmohamed, M. A., Kim, S. H., Tong, Y., Jang, M. H., Wong, C. O. (2025). Endolysosomal processing of neuron-derived signaling lipids regulates autophagy and lipid droplet degradation in astrocytes. Nat Commun, 16(1):5073 PubMed ID: 40450042
Summary: Dynamic regulation of metabolic activities in astrocytes is critical to meeting the demands of other brain cells. During neuronal stress, lipids are transferred from neurons to astrocytes, where they are stored in lipid droplets (LDs). However, it is not clear whether and how neuron-derived lipids trigger metabolic adaptation in astrocytes. This study uncovered an endolysosomal function that mediates neuron-astrocyte transcellular lipid signaling. Tweety homolog 1 (TTYH1) was identified as an astrocyte-enriched endolysosomal protein that facilitates autophagic flux and LD degradation. Astrocyte-specific deletion of mouse Ttyh1 and loss of its Drosophila ortholog tweety) lead to brain accumulation of neutral lipids. Computational and experimental evidence suggests that a TTYH1 mediates endolysosomal clearance of ceramide 1-phosphate (C1P), a sphingolipid that dampens autophagic flux and LD breakdown in mouse and human astrocytes. Furthermore, neuronal C1P secretion induced by inflammatory cytokine interleukin-1β causes TTYH1-dependent autophagic flux and LD adaptations in astrocytes. These findings reveal a neuron-initiated signaling paradigm that culminates in the regulation of catabolic activities in astrocytes. | Rosenthal, J. S., Zhang, D., Yin, J., Long, C., Yang, G., Li, Y., Lu, Z., Li, W. P., Yu, Z., Li, J., Yuan, Q. (2025). Molecular organization of central cholinergic synapses. Proc Natl Acad Sci U S A, 122(17):e2422173122 PubMed ID: 40273107
Summary: Synapses have undergone significant diversification and adaptation, contributing to the complexity of the central nervous system. Understanding their molecular architecture is essential for deciphering the brain's functional evolution. While nicotinic acetylcholine receptors (nAchRs) are widely distributed across metazoan brains, their associated protein networks remain poorly characterized. Using in vivo proximity labeling, this study generated proteomic maps of subunit-specific nAchR interactomes in developing and mature Drosophila brains. The findings reveal a developmental expansion and reconfiguration of the nAchR interactome. Proteome profiling with genetic perturbations showed that removing individual nAchR subunits consistently triggers compensatory shifts in receptor subtypes, highlighting mechanisms of synaptic plasticity. The Rho-GTPase regulator Still life (Sif) was identified as a key organizer of cholinergic synapses, with loss of Sif disrupting their molecular composition and structural integrity. These results provide molecular insights into the development and plasticity of central cholinergic synapses, advancing understanding of synaptic identity conservation and divergence. |
| Hoagland, A., Schultz, R., Cai, Z., Newman, Z. L., Isacoff, E. Y. (2025). Behavioral resilience via dynamic circuit firing homeostasis.Proc Natl Acad Sci U S A, 122(18):e2421386122 PubMed ID: 40299703
Summary: Homeostatic regulation ensures stable neural circuit output under changing conditions. This study found that in Drosophila larval neuromuscular junction, either presynaptic weakening due to perturbation of transmitter release or postsynaptic weakening due to perturbation of glutamate receptors at synapses between motor neuron (MN) and muscle has little impact on locomotion, suggesting a nonsynaptic compensatory mechanism. In vivo imaging shows that five different forms of synaptic weakening increase the duration of activity bouts in type I MNs. Strikingly, this compensation is input selective: occurring only in the tonic type Ib MN, not the phasic type Is MN that innervates the same muscle. Moreover, an inhibitory class of central pre-MNs that innervates the tonic-but not phasic-input decreases in activity. The adjustment in activity occurs remarkably quickly: within minutes of synapse perturbation. It is proposed that MN firing is dynamically regulated by two coordinated mechanisms: a cell-autonomous adjustment of MN excitability and a circuit adjustment of inhibitory central drive. The input selectivity of this process suggests homeostatic adjustment to maintain tonic drive but hold constant the phasic drive that organizes locomotory wave patterns. | Kakanj, P., Bonse, M., Kshirsagar, A., Gokmen, A., Gaedke, F., Sen, A., Molla, B., Vogelsang, E., Schauss, A., Wodarz, A., Pla-Martin, D. (2025). Retromer promotes the lysosomal turnover of mtDNA. Sci Adv, 11(14):eadr6415 PubMed ID: 40184468
Summary: Mitochondrial DNA (mtDNA) is exposed to multiple insults produced by normal cellular function. Upon mtDNA replication stress, the mitochondrial genome transfers to endosomes for degradation. Using proximity biotinylation, this study found that mtDNA stress leads to the rewiring of the mitochondrial proximity proteome, increasing mitochondria's association with lysosomal and vesicle-related proteins. Among these, the retromer complex, particularly VPS35, plays a pivotal role by extracting mitochondrial components. The retromer promotes the formation of mitochondrial-derived vesicles shuttled to lysosomes. The mtDNA, however, directly shuttles to a recycling organelle in a BAX-dependent manner. Moreover, using a Drosophila model carrying a long deletion on the mtDNA (ΔmtDNA), this study found that ΔmtDNA activates a specific transcriptome profile to counteract mitochondrial damage. Here, Vps35 expression restores mtDNA homoplasmy and alleviates associated defects. Hence, this study has demonstrated the existence of a previously unknown quality control mechanism for the mitochondrial matrix and the essential role of lysosomes in mtDNA turnover to relieve mtDNA damage. |
Thursday March 19th - Disease Models |
| Strachan, E. L., Dillon, E. T., Sullivan, M., Glennon, J. C., Peyrel, A., Sarniguet, J., Dubois, K., Delprat, B., Kennedy, B. N., O'Sullivan, N. C. (2025). Novel in vivo models of autosomal optic atrophy reveal conserved pathological changes in neuronal mitochondrial structure and function. Faseb j, 39(7):e70497 PubMed ID: 40202868
Summary: Autosomal optic atrophy (AOA) is a form of hereditary optic neuropathy characterized by the irreversible and progressive degermation of the retinal ganglion cells. Most cases of AOA are associated with a single dominant mutation in OPA1, which encodes a protein required for fusion of the inner mitochondrial membrane. It is unclear how loss of OPA1 leads to neuronal death, and despite ubiquitous expression appears to disproportionately affect the RGCs. This study introduces two novel in vivo models of OPA1-mediated AOA, including the first developmentally viable vertebrate Opa1 knockout (KO). These models allow for the study of Opa1 loss in neurons, specifically RGCs. Though survival is significantly reduced in Opa1 deficient zebrafish and Drosophila, both models permit the study of viable larvae. Moreover, zebrafish Opa1 KO larvae show impaired visual function but unchanged locomotor function, indicating that retinal neurons are particularly sensitive to Opa1 loss. Proteomic profiling of both models reveals marked disruption in protein expression associated with mitochondrial function, consistent with an observed decrease in mitochondrial respiratory function. Similarly, mitochondrial fragmentation and disordered cristae organization were observed in neuronal axons in both models highlighting Opa1's highly conserved role in regulating mitochondrial morphology and function in neuronal axons. Importantly, in Opa1 deficient zebrafish, mitochondrial disruption and visual impairment precede degeneration of RGCs. These novel models mimic key features of AOA and provide valuable tools for therapeutic screening. These findings suggest that therapies enhancing mitochondrial function may offer a potential treatment strategy for AOA. | Stephens, M. C., Li, J., Mair, M., Moore, J., Zhu, K., Tarkunde, A., Amoh, B., Perez, A. M., Bhakare, A., Guo, F., Shulman, J. M., Al-Ramahi, I., Botas, J. (2025). Computational and functional prioritization identifies genes that rescue behavior and reduce tau protein in fly and human cell models of Alzheimer disease. Am J Hum Genet, 112(5):1081-1096 PubMed ID: 40215969
Summary: Genome-wide association studies (GWASs) in Alzheimer disease (AD) have uncovered over 70 loci significantly associated with AD risk, but identifying the true causal gene(s) at these loci requires systematic functional validation that is rarely performed due to limitations of time and cost. This study disintegrated transcriptome-wide association study (TWAS) with colocalization analysis, fine-mapping, and additional annotation of AD GWAS variants to identify 123 genes at known and suggestive AD risk loci. A comparison with human AD brain transcriptome data confirmed that many of these candidate genes are dysregulated in human AD and correlate with neuropathology. All available orthologs were studied in two well-established Drosophila AD models that express either wild-type tau or secreted β-amyloid (β42). Experimental perturbation of the 60 available candidates pinpointed 46 that modulated neuronal dysfunction in one or both fly models. The effects of 18 of these genes were concordant with the TWAS prediction, such that the direction of misexpression predicted to increase AD risk in humans exacerbated behavioral impairments in the AD fly models. Reversing the aberrant down- or upregulation of 11 of these genes (MTCH2, ELL, TAP2, HDC, DMWD, MYCL, SLC4A9, ABCA7, CSTF1, PTK2B, and CD2AP) proved neuroprotective in vivo. MTCH2 was further studied, and it was found to regulate steady-state Tau protein levels in the Drosophila brain and reduces Tau accumulation in human neural progenitor cells. This systematic, integrative approach effectively prioritizes genes at GWAS loci and reveals promising AD-relevant candidates for further investigation as risk factors or targets for therapeutic intervention. |
| Sivanantharajah, L., Mudher, A., Shepherd, D. (2025). Examining the vulnerability of adult neuron subtypes to tau-mediated toxicity in Drosophila. Transl Psychiatry, 15(1):127 PubMed ID: 40188067
Summary: Selective vulnerability of nerve cells is a feature of neurodegenerative disease. To date, animal models have been limited to examining pathogenic protein expression in broad or heterogeneous neuronal populations. Consequently, noted pathological hallmarks represent an average of disease phenotypes over multiple neuron types, rather than exact measures of individual responses. This study targeted gene expression to small, precisely defined and homogenous neuronal populations in the Drosophila melanogaster central nervous system (CNS), allowing dissection of selective vulnerability of single types of neurons with single-neuron resolution. Using cellular degeneration as a readout for vulnerability, this study found while all neurons were affected by tau some neuron types were more affected (vulnerable) than others (resilient). The Tau-mediated pathogenic effects fell on a spectrum, demonstrating that neurons in the fly CNS are differentially vulnerable to Tau pathology. Mechanistically, total Tau levels did not correlate with vulnerability; rather, the best correlatives of degeneration were significant age-dependent increases in phospho-Tau levels in the same neuron type, and Tau mislocalisation into dendrites. Lastly, this study found that Tau phosphorylation in vulnerable neuron types correlated with downstream vesicular and mitochondrial trafficking defects. However, all vulnerable neuron types did not show the same pattern, suggesting multiple paths to degeneration. Beyond highlighting the heterogeneity of neuronal responses to Tau in determining vulnerability, this work provides a new, high-resolution, tractable model for studying the age-dependent effects of Tau, or any pathogenic protein, on postmitotic neurons with sub-cellular resolution. | Wu, K., Zhou, J., Tang, Y., Zhang, Q., Xiong, L., Li, X., Zhuo, Z., Luo, M., Yuan, Y., Liu, X., Zhong, Z., Guo, X., Yu, Z., Sheng, X., Luo, G., Chen, H. (2025). Werner syndrome exonuclease promotes gut regeneration and causes age-associated gut hyperplasia in Drosophila. PLoS Biol, 23(4):e3003121 PubMed ID: 40261911
Summary: Human Werner syndrome (adult progeria, a well-established model of human aging) is caused by mutations in the Werner syndrome (WRN) gene. However, the expression patterns and functions of WRN in natural aging remain poorly understood. Despite the link between WRN deficiencies and progeria, analyses of human colon tissues, mouse crypts, and Drosophila midguts revealed that WRN expression does not decrease but rather increases in intestinal stem cells (ISCs) with aging. Mechanistically, this study found that the Drosophila WRN homologue (WRNexo) binds to Heat shock 70-kDa protein cognate 3 (Hsc70-3/Bip) to regulate the unfolded protein response of the endoplasmic reticulum (UPRER). Activation of the WRNexo-mediated UPRER in ISCs is required for ISC proliferation during injury repair. However, persistent DNA damage during aging leads to chronic upregulation of WRNexo in ISCs, where excessive WRNexo-induced ER stress drives age-associated gut hyperplasia in Drosophila. This study reveals how elevated WRNexo contributes to stem cell aging, providing new insights into organ aging and the pathogenesis of age-related diseases, such as colon cancer. |
| Shen, Y., Maxson, R., McKenney, R. J., Ori-McKenney, K. M. (2025). Microtubule acetylation is a biomarker of cytoplasmic health during cellular senescence. bioRxiv, PubMed ID: 40236247
Summary: Cellular senescence is marked by cytoskeletal dysfunction, yet the role of microtubule post-translational modifications (PTMs) remains unclear. This study demonstrates that microtubule acetylation increases during drug-induced senescence in human cells and during natural aging in Drosophila. Elevating acetylation via HDAC6 inhibition or α TAT1 overexpression in BEAS-2B cells disrupts anterograde Rab6A vesicle transport, but spares retrograde transport of Rab5 endosomes. Hyperacetylation results in slowed microtubule polymerization and decreased cytoplasmic fluidity, impeding diffusion of micron-sized condensates. These effects are distinct from enhanced detyrosination, and correlate with altered viscoelasticity and resistance to osmotic stress. Modulating cytoplasmic viscosity reciprocally perturbs microtubule dynamics, revealing bidirectional mechanical regulation. Senescent cells phenocopy hyperacetylated cells, exhibiting analogous effects on transport and microtubule polymerization. These findings establish acetylation as a biomarker for cytoplasmic health and a potential driver of age-related cytoplasmic densification and organelle transport decline, linking microtubule PTMs to biomechanical feedback loops that exacerbate senescence. This work highlights the role of acetylation in bridging cytoskeletal changes to broader aging hallmarks. | Yang, Y., Mayo, A., Levy, T., Raz, N., Shenhar, B., Jarosz, D. F., Alon, U. (2025). Compression of morbidity by interventions that steepen the survival curve. Nat Commun, 16(1):3340 PubMed ID: 40199852
Summary: Longevity research aims to extend the healthspan while minimizing the duration of disability and morbidity, known as the sickspan. Most longevity interventions in model organisms extend healthspan, but it is not known whether they compress sickspan relative to the lifespan. This study presents a theory that predicts which interventions compress relative sickspan, based on the shape of the survival curve. Interventions such as caloric restriction that extend mean lifespan while preserving the shape of the survival curve, are predicted to extend the sickspan proportionally, without compressing it. Conversely, a subset of interventions that extend lifespan and steepen the shape of the survival curve are predicted to compress the relative sickspan. This is explained to be based on the saturating-removal mathematical model of aging, and present evidence from longitudinal health data in mice, Caenorhabditis elegans and Drosophila melanogaster. This theory was applied to identify potential interventions for compressing the sickspan in mice, and to combinations of longevity interventions. This approach offers potential strategies for compressing morbidity and extending healthspan. |
Monday March 16th - Gonads |
| Yu, J., Huang, Q., Fu, Y., He, L., Shen, C., Chen, X., Li, Z., Li, J., Wang, C., Wang, X., Yang, B., Lin, Z., Qiao, C., Tan, X., Yang, X., Chen, H., Zheng, Y., Zheng, B., Sun, F. (2025). Multi-omics integration reveals Vha68-3 as a testicular aging-specific factor that coordinates spermatid elongation through mitochondrial metabolic homeostasis. Cell Mol Biol Lett, 30(1):58 PubMed ID: 40346547
Summary: Testicular aging has profound effects on spermatogenesis, sperm function, and the spermatogenic microenvironment, contributing to reduced male fertility. However, the precise molecular mechanisms by which mitochondria influence spermiogenesis during aging still remain largely unclear. Vha68-3 KO flies were generated using the CRISPR/Cas9 technique. Testicular phenotypes and functions were mainly observed through immunofluorescence staining and transmission electron microscopy. Multi-omics study was mainly conducted through single-cell RNA sequencing and transcriptome-metabolomics association analysis. Vha68-3 binding proteins were identified via liquid chromatography-tandem mass spectrometry. The therapeutic potential of modulating mitochondrial metabolism for testicular aging mainly relied on the dietary intake of related compounds in fruit flies. This study identified Vha68-3, a testis-specific subunit of the V-type adenosine triphosphate (ATP) synthase, predominantly localized in the tails of elongated spermatids, as a key age-related regulator of male fertility and spermatid elongation in Drosophila testes. Crucially, Vha68-3 deficiency impaired mitochondrial homeostasis in elongated spermatids during testicular aging. Through a multi-omics approach, including single-cell transcriptomics, protein interaction mapping of Vha68-3, and transcriptome-metabolome integration, pyruvate metabolism was identified as a critical pathway disrupted by Vha68-3 deficienc. Moreover, dietary supplementation with pyruvate (PA), S-lactoylglutathione (SLG), and phosphoenolpyruvate (PEP) effectively alleviated mitochondrial dysfunction and testicular aging linked to Vha68-3 deficiency. These findings uncover novel mechanisms by which mitochondrial metabolism regulates spermatid elongation, and potential therapeutic strategies were identified to combat mitochondrial metabolic disorders in aging testes. | Zike, A. B., Abel, M. G., Fleck, S. A., DeWitt, E. D., Weaver, L. N. (2025). Estrogen-related receptor is required in adult Drosophila females for germline stem cell maintenance.. Dev Biol, 524:132-143 PubMed ID: 40348318
Summary: Adult tissue function is dependent on intrinsic factors that mediate stem cell self-renewal and proliferation in response to changes in physiology and the environment. The estrogen-related receptor (ERR) subfamily of orphan nuclear receptors are major transcriptional regulators of metabolism and animal physiology. In mammals, ERRs (NR3B1, NR3B2, NR3B3) have roles in regulating mitochondrial biosynthesis, lipid metabolism, as well as stem cell maintenance. The sole Drosophila ERR ortholog promotes larval growth by establishing a metabolic state during the latter half of embryogenesis. In addition, ERR is required in adult Drosophila males to coordinate glycolytic metabolism with lipid synthesis and within the testis to regulate spermatogenesis gene expression and fertility. Despite extensive work characterizing the role of ERR in Drosophila metabolism, whether ERR has a conserved requirement in regulating stem cell behavior has been understudied. To determine whether ERR regulates stem cell activity in Drosophila, the established adult female germline stem cell (GSC) lineage was used as a model. Whole-body ERR knockout in adult females using conditional heat shock-driven FLP-FRT recombination was found to significantly decreases GSC number and glycolytic enzyme expression in GSCs. In addition, ERR activity was found to be required cell-autonomously in the adult female germline for maintenance of GSCs; whereas ERR regulation of GSCs is independent of its activity in adult female adipocytes. These results highlight an ancient and conserved role for ERRs in the regulation of stem cell self-renewal. |
| Mercer, M., Dasgupta, A., Pawlowski, K., Buszczak, M. (2025). Bourbon and Mycbp function with Otu to promote Sxl protein expression in the Drosophila female germline. Proc Natl Acad Sci U S A, 122(15):e2426524122 PubMed ID: 40215271
Summary: In Drosophila ovaries, germ cells differentiate through several stages of cyst development before entering meiosis. This early differentiation program depends on both the stepwise deployment of specific regulatory mechanisms and on maintenance of germline sexual identity. The study of female sterile mutations that result in formation of germ cell tumors has been invaluable in identifying the mechanisms that control these developmental events. This study characterized the germ cell-enriched gene bourbon (bbn), null mutants of which cause the formation of a mixture of agametic ovarioles and cystic germ cell tumors. Proteomic analysis found Bbn forms a complex with Ovarian tumor (Otu), a protein previously linked with regulation of the sex determination factor Sex lethal (Sxl), and the Drosophila ortholog of c-Myc binding protein (Mycbp). Loss of Mycbp also results in the formation of cystic germ cell tumors. Bbn promotes the stability of Otu and fosters interactions between Otu and Mycbp. Germ cells from bbn and Mycbp mutants display a loss of Sxl expression specifically in the germline. Transgenic rescue experiments show the bbn sterile phenotype is independent from Sxl splicing defects. Further evidence suggests Otu physically interacts with and promotes Sxl protein stability. This function does not depend on Otu's deubiquitinase activity. Last, this study found the human orthologs of Otu and Mycbp, OTUD4, and MYCBP, also physically interact, suggesting conservation of function. Together these data provide insights into how a conserved complex promotes the germline expression of Sxl protein and the differentiation of Drosophila germ cells. | Tindell, S. J., Boeving, A. G., Aebersold, J., Arkov, A. L. (2025). Multiple domains of scaffold Tudor protein play non-redundant roles in Drosophila germline. bioRxiv, PubMed ID: 40166263
Summary: Scaffold proteins play crucial roles in subcellular organization and function. In many organisms, proteins with multiple Tudor domains are required for the assembly of membraneless RNA-protein organelles (germ granules) in germ cells. Tudor domains are protein-protein interaction modules which bind to methylated polypeptides. Drosophila Tudor protein contains eleven Tudor domains, which is the highest number known in a single protein. The role of each of these domains in germ cell formation has not been systematically tested and it is not clear if some domains are functionally redundant. Using CRISPR methodology, this study generated mutations in several uncharacterized Tudor domains and showed that they all caused defects in germ cell formation. Mutations in individual domains affected Tudor protein differently causing reduction in protein levels, defects in subcellular localization and in the assembly of germ granules. These data suggest that multiple domains of Tudor protein are all needed for efficient germ cell formation highlighting the rational for keeping many Tudor domains in protein scaffolds of biomolecular condensates in Drosophila and other organisms. |
| Sanghvi, K., Shandilya, S., Brown, A., Todorova, B., Jahn, M., Gascoigne, S. J. L., Camilleri, T. L., Pizzari, T., Sepil, I. (2025). Reproductive output of old males is limited by seminal fluid, not sperm number. Evol Lett, 9(2):282-291 PubMed ID: 40191416
Summary: Male reproductive senescence is typically characterized by a decline in the number of sperm produced and transferred by old males, a phenomenon that may be exacerbated in polygynous species where males mate multiply. However, males also transfer seminal fluid to females, and little is known about its role in modulating male reproductive senescence. Here, we explore the contributions of sperm and seminal fluid towards male reproductive senescence in a series of sequential matings, using Drosophila melanogaster. As expected, old males produce fewer offspring than young males. However, this pattern is not driven by sperm limitation: old males have more sperm and transfer similar numbers to females, compared to young males. Instead, females storing fewer sperm of old males compared to that of young males, over a long term, drives male reproductive senescence. It was shown that it is possible to mitigate the age-related decline in male reproductive output by supplementing females with the seminal fluid of a young male, before she mates with an old male. Similarly, the reduction in reproductive output across sequential matings is alleviate by supplementing females with seminal fluid. These findings highlight that seminal fluid, rather than sperm number, limits reproductive success in old or multiply mating males, highlighting its underappreciated role in reproductive aging. | Harsh, S., Liu, H. Y., Bhaskar, P. K., Rushlow, C., Bach, E. A. (2025). The pioneer factor Zelda induces male-to-female somatic sex reversal in adult tissues. bioRxiv, PubMed ID: 40236223
Summary: Somatic sex identity must be maintained throughout adulthood for tissue function. Adult somatic stem cells in the Drosophila testis (i.e., CySCs) lacking the transcription factor Chinmo are reprogrammed to their ovarian counterparts by induction of female-specific Tra (F), but this is not mechanistically understood. Pioneer factors play central roles in direct reprogramming, and many upregulated genes in chinmo-/- CySCs contain binding sites for the pioneer factor Zelda (Zld). microRNAs repress zld mRNA in wild type CySCs, but they are downregulated after Chinmo loss, allowing for zld mRNA translation. Zld depletion from chinmo-/- CySCs suppresses feminization, and ectopic Zld induces Tra (F) and feminizes wild-type CySCs. qkr58E-2 and ecdysone receptor ( EcR ), direct Zld targets in the embryo, are female-biased in adult gonads and upregulated in chinmo-/- CySCs. The RNA-binding protein Qkr58E-2 produces Tra (F), while EcR promotes female-biased gene expression. Ectopic Zld feminizes adult male adipose tissue, demonstrating that Zld can instruct female and override male identity in adult XY tissues. |
Thursday March 12th - Larval and adult neural development, structure, and function |
| 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. |
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