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Current papers in developmental biology and gene function
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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 2023 December 2022 December 2021 December 2020 | Nikolenko, J. V., Georgieva, S. G. (2025). MLE (DHX9) Helicase Regulates the Expression of Constitutive and Inducible Isoforms of the Conserved Nuclear Receptor FTZ-F1 (NR5A3)]. Mol Biol (Mosk), 59(2):266-276 PubMed ID: 40558038
Summary: In addition to participating in dosage compensation, the MLE helicase in D. melanogaster performs many functions in the regulation of gene expression, as does its human ortholog DHX9. Many of these functions are evolutionarily conserved and poorly explored. MLE has previously been shown to be involved in the regulation of inducible transcription of the ftz-f1 gene encoding the evolutionarily conserved nuclear receptor NR5A3. The ftz-f1 gene also encodes a constitutive transcript synthesized from an alternative promoter. The present work is devoted to the investigation of the role of MLE in the regulation of constitutive transcription of the fftz-f1 gene. This work shows that in S2 cell culture, MLE binds to the constitutive promoter and controls both inducible and constitutive transcription of the ftz-f1 gene. A novel MLE-binding cis- regulatory element of the ftz-f1 gene, enhancer 663, was identified. Using chromosome conformation capture technique the interaction of enhancer 663 with constitutive and inducible promoters of ftz-f1 gene in S2 cell culture was demonstrated. Examination of enhancer 663 histone H3 acetylation showed that it is involved in the activity of both promoters. Knockdown of MLE in S2 cell culture causes an increase in constitutive transcription. The effect of MLE on transcription beyond dosage compensation in vivo at the adult stage was shown for the first time. It was shown that at the adult stage MLE binds to both inducible and constitutive promoters and to enhancer 663. Mutation in the mle gene leads to increased expression of both transcripts of the ftz-f1 gene in females. The data obtained are important for understanding and further study of the evolutionarily conserved functions of MLE and its human ortholog DHX9. | Dong, P., Li, Y., Wang, Y., Zhao, Q., Lu, T., Chen, J., Guo, T., Ma, J., Yang, B., Wu, H., Huang, H. (2025). Fat body-derived cytokine Upd2 controls disciplined migration of tracheal stem cells in Drosophila. Elife, 13 PubMed ID: 40485562
Summary: Coordinated activation and directional migration of adult stem cells are essential for maintaining tissue homeostasis. Drosophila tracheal progenitors are adult stem cells that migrate posteriorly along the dorsal trunk to replenish degenerating branches that disperse the fibroblast growth factor mitogen. However, it is currently unknown how the overall anterior-to-posterior directionality of such migration is controlled. This study shows that individual progenitor cells migrate together in a concerted, disciplined manner, a behavior that is dependent on the neighboring fat body. Thehe fat body-derived cytokine, Upd2, was identified in targeting and inducing JAK/STAT signaling in tracheal progenitors to maintain their directional migration. Perturbation of either Upd2 production in fat body or JAK/STAT signaling in trachea causes aberrant bidirectional migration of tracheal progenitors. JAK/STAT signaling promotes the expression of genes involved in planar cell polarity leading to asymmetric localization of Fat in progenitor cells. Evidence is provided that Upd2 transport requires Rab5- and Rab7-mediated endocytic sorting and Lbm-dependent vesicle trafficking>. This study thus uncovers an inter-organ communication in the control of disciplined migration of tracheal progenitor cells, a process that requires vesicular trafficking of fat body-derived cytokine Upd2 and JAK/STAT signaling-mediated activation of PCP genes. |
| Lancaster, C., Manhart, A., Pichaud, F. (2025). Integrins coordinate basal surface contraction and oriented cell growth to enable thickening of a curved epithelium.. Curr Biol, PubMed ID: 40532702
Summary: During development, tissues undergo morphogenesis to achieve their final form. This process relies on coordinated cell shape changes, which have predominantly been studied in one plane, at the apical (top) surface of developing tissues. However, tissues are three dimensional, often exhibiting deformations along multiple axes. To understand how morphogenesis is coordinated across tissue axes, the genetically amenable Drosophila retina, a curved, dome-shaped epithelium, as a model system, was used. Using intravital imaging, this study found that retinal curvature is induced early in development. Modeling early retinal development with a vertex model suggests that this curvature arises from differential planar growth between the apical and basal tissue surfaces. In addition, mechanical perturbation experiments revealed that inside-out fluid pressure plays a crucial role in promoting this curvature. Further combining computational modeling, genetic perturbations, and force-inference experiments, this study demonstrate that uniform thickening of the curved retinal epithelium requires coordination of two key processes: growth, promoting cell elongation along the apical-basal axis of the tissue, and basal surface contraction. Remarkably, inhibiting basal surface contraction-both in silico and through genetic manipulations targeting the basal surface receptor integrin and non-muscle myosin-II-prevented cell elongation. It is concluded that thickening of a curved epithelium, like the Drosophila retina, requires both integrin and non-muscle myosin-II to coordinate basal surface contraction and cell growth along the apical-basal axis of the tissue. | Arias, R. A., Mavromatakis, Y. E., Tomlinson, A. (2025). Roles played by Enhancer of split transcription factors in Drosophila R7 photoreceptor specification. Dev Biol, 526:38-51 PubMed ID: 40578501
Summary: When a cell receives multiple developmental signals simultaneously, the intracellular transduction pathways triggered by those signals are coincidentally active. How then, do the cells decode the information contained within those multiple active pathways to derive a precise developmental directive? The specification of the Drosophila R7 photoreceptor is a classic model system for investigating such questions. The R7 fate is specified by the combined actions of the Notch (N) and receptor tyrosine kinase (RTK) signaling pathways. The two pathways cross-communicate in an integrative mechanism and also supply information independently of each other. Collectively, this information is summed to provide an unambiguous directive for the R7 fate. The goal of this study is to understand these mechanisms. How N activity represses transcription of the phyllopod gene in the process of information integration with the RTK pathway, and how it represses expression of the seven-up gene in an independent mechanism needed for R7 fate. This study describes how N activity achieves these transcriptional repressions and identify Enhancer of Split transcription factors as the mediators of its functions. |
| Chatterjee, M., Yu, X. Y., Brady, N. K., Amendola, C., Hatto, G. C., Reed, R. D. (2025). mirror determines the far posterior domain in butterfly wings. Elife, 13 PubMed ID: 40557921
Summary: Insect wings, a key innovation that contributed to the explosive diversification of insects, are recognized for their remarkable variation and many splendid adaptations. Classical morphological work subdivides insect wings into several distinct domains along the anteroposterior (AP) axis, each of which can evolve relatively independently to produce the myriad forms seen in nature. Important insights into AP subdivision of insect wings come from work in Drosophila melanogaster; however, they do not fully explain the diversity of AP domains observed across broad-winged insects. This study shows that the transcription factor mirror acts as a selector gene to differentiate a far posterior domain in the butterfly wing, classically defined as the vannus, and has effects on wing shape, scale morphology, and color pattern. The results support models of how selector genes may facilitate evolutionarily individuation of distinct AP domains in insect wings outside of Drosophila and suggest that the D. melanogaster wing blade has been reduced to represent only a portion of the archetypal insect wing. | Rodier, C., Estabrook, I. D., Chan, E. H., Rice, G., Loreau, V., Raunser, S., Gorlich, D., Friedrich, B. M., Schnorrer, F. (2025). Muscle growth by sarcomere divisions. Sci Adv, 11(28):eadw9445 PubMed ID: 40632866
Summary: The sarcomere is the elementary contractile unit of muscles. Adult muscle cells are large and chain thousands of sarcomeres into long periodic myofibrils that attach to the skeleton. During development, muscle cells must increase in length to maintain the mechanical connection to the growing skeleton. How muscles add new sarcomeres to facilitate muscle growth is unknown. Using live imaging and high-throughput image analysis, this stuedy has now tracked the sarcomere components during the developmental growth of Drosophila muscle and found that individual sarcomeres divide along the myofibril tension axis into daughter sarcomeres. This way, new sarcomeres can be inserted into contractile and mechanically intact myofibrils. It is proposed that sarcomere division is triggered by tension and local sarcomere damage originating from skeletal growth and muscle contractions. Sarcomere divisions repair damaged sarcomeres, ensure their mechanical integrity, and synchronize sarcomere addition with skeletal growth during animal development. |
Wednesday September 24nd - Disease Model |
| Bi, H., Wan, Y., Zhao, R., Pan, S., Luan, M., Wu, W., Qiu, Y., Yu, J., Sun, Y., Wei, L., Chen, J., Li, F., Sun, W., Wang, L., Wang, X., Zhao, W., Wang, D., Tuo, H., Zhang, Y., Zhang, W., Huang, Y., Yuan, Y., Hong, D., Wang, Z., Deng, J. (2025). Intronic VNTRs downregulate expression of HSF1 and confer genetic risk of essential tremor. Brain, PubMed ID: 40581632
Summary: Essential tremor (ET) is a highly prevalent movement disorder characterized by high heritability. However, the genetic basis of this disease remains largely unknown. Understanding the genetic causes of ET is crucial for unraveling its pathogenesis and developing targeted therapies. This study aimed to investigate tandem repeats in a Chinese cohort of ET pedigrees. To explore the genetic causes of ET, 165 Chinese ET pedigrees were enrolled, and whole-exome sequencing (WES) as well as long-read sequencing (LRS) were performed within this cohort. Quantitative real-time polymerase chain reaction (RT-qPCR) and Western blot analyses were employed to assess HSF1 expression levels. Transgenic Drosophila model and induced pluripotent stem cells (iPSCs) were constructed to investigate the pathogenic role of HSF1 in ET. This study identified the expanded variable number of tandem repeats (VNTRs) in intron 10 of HSF1. LRS revealed two repeat configurations consisting of CCCCGCNCCGCCT and CCNCGCCT in this VNTR loci. Expanded VNTRs alleles were highly enriched in ET affected individuals, and VNTRs length was positively correlated with disease severity. The intronic repeat expansions downregulated HSF1 expression in affected individuals, indicating its loss-of-function in ET. Consistently, RNAi knockdown of HSF1 homolog in Drosophila led to leg and head shaking and age-dependent movement deficits, recapitulating the ET phenotype in fly model. iPSCs derived from the ET affected individual carrying expanded VNTRs in the HSF1 gene exhibited significantly reduced expression of HSF1 compared to control iPSCs. Bulk RNA-sequencing analysis of these iPSCs revealed that diminished HSF1 expression resulted in the downregulation of genes associated with GABAergic synapse function. In conclusion, this study suggests that impaired GABAergic signaling may play a critical role in the pathogenesis of HSF1-related ET. These findings provide new information on the etiology of ET and highlight the role of HSF1 in human genetic disorder. | Dong, K., Burch, A., Huang, K. (2025). Application of deep learning for multi-scale behavioral analysis in SNCA E46K Parkinson's disease Drosophila. Cogn Neurodyn, 19(1):105 PubMed ID: 40605911
Summary: Drosophila melanogaster is widely used as a model organism in Parkinson's disease research. However, due to the complexity of motion capture and the challenges of quantitatively assessing spontaneous behavior in Drosophila melanogaster, it remains technically difficult to identify symptoms of Parkinson's disease within Drosophila based on objective spontaneous behavioral characteristics. This study presents an automated multi-scale behavioral phenotyping pipeline that classifies phenotypes related to Parkinson's disease using motion features extracted from pose estimation data of wild-type and Synuclein Alpha E46K mutant Drosophila melanogaster. Locomotor activity was recorded in a custom-designed 3D-printed behavioral trap, and body kinematics were analyzed using a markerless pose estimation tool to extract numerical features such as movement speed, tremor-like oscillations, and limb motion patterns. Beyond kinematic analysis, this study applied unsupervised clustering to the pose-derived trajectories to extract recurrent movement subtypes that characterize spontaneous behavioral sequences. Kinematic features alone were found to be insufficient to distinguish mutant flies from normal individuals, whereas behavioral sequence patterns captured through unsupervised clustering enabled robust group separation. Combining both feature types further enhanced classification accuracy, with the best model achieving 85%. This system provides an objective and scalable approach for analyzing behavior related to Parkinson's disease in Drosophila melanogaster, with potential applications in monitoring disease progression and screening pharmaceutical compounds. |
| Akarsu, G., MacCharles, K. R., Wong, K. K. L., Richman, J. M., Verheyen, E. M. (2025). Robinow syndrome DVL1 variants disrupt morphogenesis and appendage formation in a Drosophila disease model. Dev Dyn, PubMed ID: 40600289
Summary: Robinow syndrome is a rare developmental syndrome caused by variants in genes in Wnt signaling pathways. Previous work showed that expression of patient variants in Dishevelled 1 (DVL1: see Drosophila Dishevelled) This study further examine morphological changes that occur due to expression of DVL11519ΔT, which serves as a prototype for other pathogenic variants. Eepithelial imaginal disc development is disrupted in legs and wings and accompanied by increased cell death, without changes in cell proliferation. By inhibiting caspase-dependent cell death, this study showed that the altered epithelial morphology is not solely due to variant-induced cell death. Furthermore, alterations of components and modulators were found. Notably ectopic Mmp1 expression and tissue distortion, which is dependent on JNK signaling. An abnormal abundance of Drosophila collagen IV (Viking) in pupal wing development. Due to the complex nature of appendage development, The Bone Morphogenetic Protein pathway was also examined, and elevated signaling activity was found via the transcriptional readout dad-lacZ. | Abbigeri, M. B., Khan, M., Thokchom, B., Singh, S. R., Bhavi, S. M., Kulkarni, S. R., Harini, B. P., Reddy, G. V. S., Govindasamy, C., Almutairi, K. M., Babu, Y. R. (2025). Therapeutic evaluation of Martynia annua derived carbon dots in epileptic Drosophila model. Sci Rep, 15(1):21572 PubMed ID: 40596571
Summary: This study investigates the synthesis and characterization of Carbon dots (MA-CDs) derived from the aqueous extract of Martynia annua and examining their potential effects in an epilepsy model Drosophila melanogaster. Phytochemical analysis confirmed the presence of saponin, terpeniods, and flavanoids in the leaf extract, which facilitated the green synthesis of MA-CDs. Physicochemical characterization revealed an absorbance peak at 326 nm, the mean size of the particle was 3.17 ∓ 0.16 nm, and moderate stability (-1.6 mV). To assess the therapeutic potential of MA-CDs alongside the antiepileptic drug Carbamazepine (CBZ),behavioral and cognitive assays were conducted in para bang senseless (para(bss1)) mutants of Drosophila, a model organism for epilepsy. Seizures induced by vortex and heat shock were significantly mitigated in a dose-dependent manner in flies treated with both MA-CDs and CBZ. However, higher doses of CBZ and MA-CDs increased the climbing ability of the flies. In cognitive assays, CBZ at higher doses improved memory and learning in mutant flies, while MA-CDs also showed significant impact. MA-CDs were consumed at a higher rate than CBZ when incorporated into food. The green synthesized MA-CDs at its higher concentration has garnered its positive effect on the mutants along with the CBZ antiepileptic drug which also has shown its positive effects when different concentration of them were treated to the mutants. |
| Bar, S., Wilson, K. A., Hilsabeck, T. A. U., Alderfer, S., Dammer, E. B., Burton, J. B., Shah, S., Holtz, A., Carrera, E. M., Beck, J. N., Chen, J. H., Kauwe, G., Seifar, F., Shantaraman, A., Tracy, T. E., Seyfried, N. T., Schilling, B., Ellerby, L. M., Kapahi, P. (2025). Neuronal glycogen breakdown mitigates tauopathy via pentose-phosphate-pathway-mediated oxidative stress reduction. Nat Metab, PubMed ID: 40588539
Summary: Tauopathies encompass a range of neurodegenerative disorders, such as Alzheimer's disease (AD) and frontotemporal lobar degeneration with tau inclusions (FTLD-tau), for which there are currently no successful treatments. This study shows impaired glycogen metabolism in the brain of a tauopathy Drosophila melanogaster model and people with AD, indicating a link between tauopathies and glycogen metabolism. The breakdown of neuronal glycogen ameliorates the tauopathy phenotypes in flies and induced pluripotent stem cell (iPSC)-derived neurons from people with FTLD-tau. Glycogen breakdown redirects glucose flux to the pentose phosphate pathway and alleviates oxidative stress. These findings uncover a critical role for the neuroprotective effects of dietary restriction (DR) by increasing glycogen breakdown. Mechanistically, a potential interaction was shown between tau protein and glycogen, suggesting a vicious cycle in which tau binding promotes glycogen accumulation in neurons, which in turn exacerbates tau accumulation which further disrupts cellular homeostasis. These studies identify impaired glycogen metabolism as a key hallmark for tauopathies and offer a promising therapeutic target in tauopathy and other neurodegenerative diseases. | Bayar, S., Seep, L., Doubkova, K., Zurkovic, J., Bulow, M. H., Kierdorf, K., Bauer, R., Thiele, C., Tavosanis, G., Hasenauer, J., Mass, E. (2025). Developmental programming by maternal obesity alters offspring lifespan and immune responses in a diet- and sex-specific manner. Cells Dev:204040 PubMed ID: 40653017
Summary: Maternal obesity is a growing health concern that predisposes offspring to metabolic dysfunction, immune system alterations, and neurodegenerative disorders. To investigate the intergenerational effects of maternal obesity, Drosophila melanogaster exposed to high-sugar (HSD) and high-fat diets (HFD) before mating were used. This study found that maternal diet-induced obesity significantly altered offspring lifespan, immune responses, and neuronal health in a sex- and diet-specific manner. Male offspring were particularly susceptible, exhibiting reduced lifespan, impaired climbing ability, and increased axonal degeneration, especially following maternal HFD exposure. Transcriptomic analyses revealed age-dependent and diet-specific changes, with males showing pronounced alterations at 50 days of age. Developmental programming of hemocytes (blood-like cells) played a crucial role in these outcomes, as knockdown of key immune pathways such as Relish and upd3 in hemocytes further influenced lifespan in a diet-specific manner. These findings highlight the complex interplay between maternal diet and immune function, underscoring the impact of maternal obesity-induced imprinting on immune cells and subsequent long-term health consequences. This study provides new insights into conserved mechanisms linking maternal metabolic health to offspring outcomes and emphasizes the continued need for animal models to understand intergenerational health impacts. |
Monday September 22nd - Tumors and Growth |
| Cong, B., Thakur, T., Uribe, A. H., Stamou, E., Gopinath, S., Sansom, O., Maddocks, O., Cagan, R. (2025). Colon cancer cells evade drug action by enhancing drug metabolism. Oncogene PubMed ID: 40634495
Summary: Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide. One key reason is the lack of durable therapies that target KRAS-dependent disease, which represents approximately 40% of CRC cases. This study used liquid chromatography/mass spectrometry (LC/MS) analyses on Drosophila CRC tumour models to identify multiple metabolites in the glucuronidation pathway-a toxin clearance pathway that impacts most drugs-as upregulated in trametinib-resistant RAS/APC/P53 ("RAP") tumours compared to trametinib-sensitive Ras(G12V) single mutant tumours. Genetic inhibition of different steps along the glucuronidation pathway strongly reversed RAP resistance to trametinib; conversely, elevating glucuronidation pathway activity was sufficient to direct trametinib resistance in Ras(G12V) animals. Mechanistically, pairing oncogenic RAS with hyperactive WNT activity strongly elevated PI3K/AKT/GLUT signalling, which in turn directed elevated glucose uptake and glucuronidation; the data also implicate the pentose phosphate pathway in this process. Evidence is provided that this mechanism of trametinib resistance is conserved in a KRAS/APC/TP53 mouse CRC tumour organoid model. Finally, two clinically accessible approaches were identified to inhibiting drug glucuronidation: (i) blocking an initial HDAC1-mediated deacetylation step of trametinib with the FDA-approved drug vorinostat; (ii) reducing blood glucose by the alpha-glucosidase inhibitor acarbose. Overall, these observations demonstrate a key mechanism by which oncogenic RAS/WNT activity promotes increased drug clearance in CRC and provides a practical path towards abrogating drug resistance in CRC tumours. | Krabbenhoft, S. D., Masuda, T. E., Kaur, Y., Do, T. J., Jain, S. U., Lewis, P. W., Harrison, M. M. (2025). Investigating oncoprotein-mediated chromatin dysregulation in Drosophila melanogaster uncovers novel modifiers of the developmental impact of H3 K27M and EZHIP. bioRxiv, PubMed ID: 40502002
Summary: Polycomb Repressive Complex 2 (PRC2) maintains epigenetic repression through the catalysis of H3K27 trimethylation (H3K27me3), which restricts gene expression and preserves developmental gene-regulatory networks. The integrity of PRC2-mediated gene silencing depends critically on the ability of PRC2 to establish and propagate H3K27me3 beyond initial recruitment sites. The oncoproteins EZHIP and histone H3 K27M specifically inhibit this propagation by blocking the allosterically activated state of PRC2, leading to global disruption of H3K27me3 patterns and developmental abnormalities. To uncover chromatin-related pathways intersecting with PRC2 repression, a Drosophila melanogaster model was developed with tissue-specific expression of EZHIP and H3 K27M. A targeted RNAi screen of conserved chromatin regulators identified genetic modifiers that when knocked down either enhanced or suppressed developmental phenotypes driven by these PRC2 inhibitors. Strong suppressors, including the Trithorax-group proteins Ash1 and Trx, the PR-DUB complex member Asx, and the nucleoporin Nup153, restored normal development despite persistent depletion of global H3K27me3. Gene expression analyses revealed that suppression reflected reduced expression of genes aberrantly activated following PRC2 inhibition. Together, these findings highlight conserved chromatin-regulatory pathways that intersect with Polycomb to maintain transcriptional balance and support developmental homeostasis. |
| Chen, Z., Zhang, X., Deng, M., Li, C., Nguyen, T. T., Liu, M., Dou, K., Ishibashi, T., Wang, J., Yan, Y. (2025). Epigenetic reprogramming induced by key metabolite depletion is an evolutionarily ancient path to tumorigenesis. Dis Model Mech, 18(6) PubMed ID: 40523311
Summary: Tumor growth is a challenge for multicellular life forms. Contrary to human tumors, which take years to form, tumors in short-living species can arise within days without accumulating multiple mutations, raising the question whether the paths to tumorigenesis in diverse species have any commonalities. In a fly tumor model caused by loss of cell polarity genes, this study identified two key metabolic changes: first, systemic depletion of acetyl-CoA leading to a reduction in histone acetylation levels and stochastic silencing of actively transcribed genes; and second, defects in the methionine cycle causing systemic depletion of S-adenosyl methionine, which further reduces histone methylation levels and causes stochastic activation of transposons. Perturbation of the methionine metabolic process inhibits tumor growth. To understand the evolutionary origin of tumorigenesis, comparative studies of fly and human tumors were performed; human tumors with metabolic signatures similar to those of fly tumors were found to have a lower mutational load, younger patient age and lower DNA methylation levels. This study indicates that depletion of key metabolites is an evolutionarily ancient driving force for tumorigenesis. | Kong, D., Li, X., Zhao, S., Wang, C., Cai, Z., Song, S., Guo, Y., Kuang, X., Wang, X., Liu, W., Liu, P., Guo, X., Xu, W., Wang, Y., Zhao, B., Jin, B., He, L., Ma, X. (2025). Adipose tissue-secreted Spz5 promotes distal tumor progression via Toll-6-mediated Hh pathway activation in Drosophila. Embo j, PubMed ID: 40551010
Summary: Interorgan communication is vital for tissue homeostasis and health in multicellular organisms, and its disruption can lead to diseases such as cancer. Adipose tissue acts as a key endocrine center, secreting cytokines that influence remote organs. Despite clear links between obesity and increased cancer risk, the underlying mechanisms are unclear. In this study, utilizing a Drosophila genetic model combining Gal4-UAS and QF-QUAS tissue-specific transgene expression systems, it was revealed that adipose-secreted Spz5 ligand promotes distal epithelial tumor overgrowth and invasion. Mechanistically, Spz5 binds to tumor cell Toll-6 receptors, triggering the degradation of the endocytic adaptor protein AP-2α via Mib1-mediated ubiquitination. Consequently, impaired endocytosis leads to Smoothened (Smo) accumulation on the cell membrane and subsequent activation of the Hedgehog (Hh) pathway. This abnormal Hh activation synergizes with the oncogenic Yorkie (Yki) to drive tumor growth and invasion. Furthermore, tumor-derived Unpaired ligands (Upds) activate the JAK-STAT pathway in the fat bodies, which leads to Hippo pathway-dependent upregulation of spz5 expression. Thus, this study provides insights into the complex regulatory mechanisms by which systemic interorgan communication influences tumor progression. |
| Khaket, T. P., Rimal, S., Wang, X., Bhurtel, S., Wu, Y. C., Lu, B. (2024). Ribosome stalling during c-myc translation presents actionable cancer cell vulnerability. PNAS nexus, 3(8):pgae321 PubMed ID: 39161732
Summary: Myc (see Drosophila Myc) is a major driver of tumor initiation, progression, and maintenance. Up-regulation of Myc protein level rather than acquisition of neomorphic properties appears to underlie most Myc-driven cancers. Cellular mechanisms governing Myc expression remain incompletely defined. This study shows that ribosome-associated quality control (RQC) plays a critical role in maintaining Myc protein level. Ribosomes stall during the synthesis of the N-terminal portion of cMyc, generating aberrant cMyc species and necessitating deployment of the early RQC factor ZNF598 to handle translational stress and restore cMyc translation. ZNF598 expression is up-regulated in human glioblastoma (GBM), and its expression positively correlates with that of cMyc. ZNF598 knockdown inhibits human GBM neurosphere formation in cell culture and Myc-dependent tumor growth in vivo in Drosophila. Intriguingly, the SARS-COV-2-encoded translational regulator Nsp1 impinges on ZNF598 to restrain cMyc translation and consequently cMyc-dependent cancer growth. Remarkably, Nsp1 exhibits synthetic toxicity with the translation and RQC-related factor ATP-binding cassette subfamily E member 1, which, despite its normally positive correlation with cMyc in cancer cells, is co-opted by Nsp1 to down-regulate cMyc and inhibit tumor growth. Ribosome stalling during c-myc translation thus offers actionable cancer cell vulnerability. | Mitchell, K. A., Vissers, J. H. A., Pojer, J. M., Brooks, E., Hilmi, A. J. S., Papenfuss, A. T., Schroder, J., Harvey, K. F. (2024). The JNK and Hippo pathways control epithelial integrity and prevent tumor initiation by regulating an overlapping transcriptome. Curr Biol, PubMed ID: 39146938
Summary: Epithelial organs maintain their integrity and prevent tumor initiation by actively removing defective cells, such as those that have lost apicobasal polarity. This study identified how transcription factors of two key signaling pathways-Jun-N-terminal kinase (JNK) and Hippo-regulate epithelial integrity by controlling transcription of an overlapping set of target genes. Targeted DamID experiments reveal that, in proliferating cells of the Drosophila melanogaster eye, the AP-1 transcription factor Jun and the Hippo pathway transcription regulators Yorkie and Scalloped bind to a common suite of target genes that promote organ growth. In defective neoplastic cells, AP-1 transcription factors repress transcription of growth genes together with the C-terminal binding protein (CtBP) co-repressor. If gene repression by AP-1/CtBP fails, neoplastic tumor growth ensues, driven by Yorkie/Scalloped. Thus, AP-1/CtBP eliminates defective cells and prevents tumor initiation by acting in parallel to Yorkie/Scalloped to repress expression of a shared transcriptome. These findings shed new light on the maintenance of epithelial integrity and tumor suppression. |
Friday September 19th - RNA, Genes and Proteins |
| Kolesnikova, T. D., Balantaeva, M. N., Pokholkova, G. V., Antonenko, O. V., Zhimulev, I. F. (2025). The key role of heterochromatin in the phenotypic manifestation of the In(1)sc8 inversion disrupting the achaete-scute complex in Drosophila melanogaster. Vavilovskii Zhurnal Genet Selektsii, 29(3):414-422 PubMed ID: 40556971
Summary: The achaete-scute complex (AS-C) is a locus approximately 90 kbp in length, containing multiple enhancers. The local expression of the achaete and scute genes in proneural clusters of Drosophila melanogaster imaginal discs results in the formation of a well-defined pattern of macrochaetae in adult flies. A wide variety of easily analyzed phenotypes, along with the direct connection between individual regulatory elements and the development of specific setae make this locus a classic model in developmental genetics. One classic AS-C allele is sc8, which arose as a result of the In(1) sc8 inversion. One breakpoint of this inversion lies between the ac and sc genes, while the second is in the pericentromeric heterochromatin of chromosome X, within satellite block 1.688. The heterochromatic position of the breakpoint raised the question of whether position effect variegation contributes to the disruption of normal locus function in the In(1)sc8 flies. However, conflicting results were obtained. Previously, this a secondary inversion, In(1)19EHet, was found that arose spontaneously in one of the stocks of the In(1)sc8 BDSC line, transferring most of the heterochromatin from the ac gene to the 19E region of the X chromosome. This study demonstrated that the In(1)19EHet inversion leads to complete rescue of the number of posterior supraalar (PSA) and partial rescue of the number of dorsocentral (DC) macrochaetes observed in the original In(1)sc8 line. The same rescue of the macrochaetes pattern was observed when the In(1)sc8 inversion was introduced into a strain with the Su(var)3-906 position effect modifier. Combining the inversion with the Rif11 mutation, a conserved factor determining late replication and underreplication, does not restore the normal pattern of bristles. These data indicate that the phenotype of flies carrying the In(1) sc8 inversion, associated with a disturbance in bristle development, is determined by the effect of heterochromatin on the distal part of the locus. This model can be used to test the influence of various factors on the position effect variegation caused by heterochromatin. Another phenotypic manifestation of In(1)sc8, a decreased proportion of males in the offspring, was independent of the proximity of the distal part of AS-C to heterochromatin and was not affected by the Rif11 mutation. | Giang, A., Martelli, F., Fusetto, R., Nero, T. L., Lueke, B., Nauen, R., Batterham, P. (2025). Functional and structural insights into P450-mediated resistance: The role of Cyp6g1 and Cyp6g2 in the metabolism of neonicotinoids in Drosophila melanogaster. Pestic Biochem Physiol, 212:106451 PubMed ID: 40500059
Summary: Insecticide-driven selection pressures have accelerated the evolution and widespread emergence of resistance in insect populations. A major mechanism underlying this resistance is the enhanced metabolic detoxification of insecticides, often mediated by the overexpression or increased activity of cytochrome P450 enzymes. Evidence indicates that the ability of these enzymes to confer resistance may have evolved from their native role in metabolising environmental xenobiotics. This suggests that insect populations may harbor multiple metabolic enzymes capable of conferring resistance, even if not specifically adapted for insecticide metabolism. To investigate this hypothesis, this study examined the well-characterised resistance gene Cyp6g1 and five closely related cytochrome P450s in Drosophila melanogaster. Using transgenic overexpression driven by the Accord promoter-responsible for elevated Cyp6g1 expression in natural populations-this study found that only Cyp6g1 and Cyp6g2 conferred resistance to the neonicotinoids imidacloprid and nitenpyram. Metabolic assays confirmed that imidacloprid resistance was mediated by the conversion of imidacloprid into 5-hydroxyimidacloprid. Additionally, field-resistant haplotypes promoting Cyp6g1 overexpression were also found to increase Cyp6g2 expression, suggesting that Cyp6g2 contributes to resistance in natural populations. Structural analysis of CYP6G1, using molecular docking and site-directed mutagenesis, identified residues Phe123 and Phe124 as critical for imidacloprid metabolism. These findings contribute to understanding of the evolutionary pathways leading to metabolic resistance and offer insights that could improve strategies for managing and mitigating insecticide resistance. |
| Moon, M., Yun, J., Pyeon, M., Yun, J., Yang, J., Yeom, H. D., Lee, G., Choi, Y. S., Lee, J., Lee, J. H. (2025). Phenethyl Acetate as an Agonist of Insect Odorant Receptor Co-Receptor (Orco): Molecular Mechanisms and Functional Insights. Int J Mol Sci, 26(11) PubMed ID: 40507781
Summary: The insect olfactory system is vital for survival, enabling the recognition and discrimination of a wide range of odorants present in the environment. This process is mediated by odorant receptors (Ors) and the highly conserved co-receptor Orco. Insect Ors are structurally distinct from mammalian olfactory receptors, a divergence that presents unique advantages for developing insect-specific pest control strategies. This study explored the molecular-level interactions between insect Ors and volatile organic compounds. Specifically, the response was investigated of Ors/Orco to phenethyl acetate (PA), a volatile compound found in the culture media of acetic acid bacteria. PA elicited activation in a concentration-dependent, reversible, and voltage-independent manner in Or1a, Or24a, and Or35a when combined with Orco, as well as in Orco homomers. Through molecular docking studies, this study determined that the PA-binding site is localized to the Orco subunit, a highly conserved protein across diverse insect taxa. To further elucidate the role of key residues in the Orco homotetramer receptor, site-directed mutagenesis was performed. A mutational analysis identified W146 and E153 as critical residues for PA binding and activation. A double-mutant Orco receptor (W146A + E153A) exhibited a significant reduction in PA-induced activation compared to the wild-type receptor. These findings indicate that PA functions as an agonist for the Drosophila melanogaster Orco receptor and highlight its potential applications in chemosensory research and insect pest management strategies. | Fudo, S., Verkhovskaya, M., Di Scala, C., Rivera, C., Kajander, T. (2025). Biophysical characterization and ion transport with cell-based and proteoliposome reconstitution assays of invertebrate K(+)-Cl(-) cotransporters. FEBS Open Bio, PubMed ID: 40509965
Summary: The cation-chloride cotransporter (CCC) family includes ion symporters that cotransport monovalent cations and Cl(-), playing a crucial role in controlling cytoplasmic ion content. K(+)-Cl(-) cotransporters (KCCs) facilitate the symport of ions across the plasma membrane. The CCCs participate in various physiological processes, such as transepithelial ion transport and regulation of cell volume. Among KCCs, KCC2 has unique and essential functions in the central nervous system. KCC from Drosophila melanogaster (DmKCC) is an ortholog of mammalian KCCs. Its critical role in neuronal transmission has been demonstrated. Also, the cnidarian Hydra vulgaris has a functional KCC (HvKCC). Comparative analyses of these transporters with vertebrate counterparts can provide insights into the mechanism of KCC ion transport, regulation, and evolution. Thus, this study purified DmKCC and HvKCC and characterized their biophysical properties using differential scanning fluorimetry and light scattering. Their functionality in cells was evaluated, and a method was developed to study ion transport with flame photometry. Further, a fluorescence-based assay for DmKCC reconstituted into proteoliposomes was developed. The activity of DmKCC was found to be dependent on Ca(2+), which is reminiscent of some other chloride transport protein families and potentially important for the KCC protein family overall. |
| Coirry, C., Manessier, J., Clot, C., Mortier, M., Fauvarque, M. O., Taillebourg, E. (2025). The Deubiquitinase USP36 Funtions Through Catalytic-Dependent and Catalytic-Independent Mechanisms in Drosophila. Genetics, PubMed ID: 40646716
Summary: Deubiquitinases (DUBs) form a specific class of proteases removing ubiquitin from target proteins. They are involved in the regulation of many cellular processes including cell growth and proliferation. Among them, USP36 is a key regulator of the oncogenic transcription factor c-Myc, preventing its degradation by the proteasome. These two proteins form an evolutionary conserved complex providing the opportunity to investigate USP36 mechanisms of action in vivo in a genetically tractable model such as Drosophila melanogaster. Null mutants of dUsp36 (scrawny) die early during larval development and exhibit severe growth defects. Strikingly, this study reports that flies expressing a catalytically inactive version of dUSP36 produced by CRISPR/Cas9 gene editing survive to adulthood with only minor growth defects, yet males are infertile. This finding indicates that dUSP36 deubiquitinating activity is dispensable for cell growth but essential for spermatogenesis. These results thus reveal that dUSP36 functions through both catalytic-dependent and catalytic-independent mechanisms, highlighting a dual mode of action with implications for the understanding of DUBs mechanism of action. | Blanco, C., Xiang, W., Boumpas, P., Buvry, E., Scorcelletti, M., Hermon, A. S., Wong, J., Merabet, S., Carnesecchi, J. (2025). Synergistic DNA and RNA binding of the Hox transcription factor Ultrabithorax coordinates splicing and shapes in vivo homeotic functions. Nucleic Acids Res, 53(12) PubMed ID: 40613713
Summary: The dual interaction of many transcription factors (TFs) with both DNA and RNA is an underexplored issue that could fundamentally reshape understanding of gene regulation. This central issue was addressed by investigating the RNA binding activity of the Drosophila Hox TF Ultrabithorax (Ubx) in alternative splicing and morphogenesis. Relying on molecular and genetic interactions, this study uncovered a homodimerisation-dependent mechanism by which Ubx regulates splicing. Notably, this mechanism enables the decoupling of Ubx-DNA and -RNA binding activity in splicing. A critical residue for Ubx-RNA binding was identified, and the essential role of Ubx-RNA binding ability for its homeotic functions was identified. Overall, this study uncovered a unique mechanism for Ubx-mediated splicing and underscore the critical contribution of synergistic DNA/RNA binding for its morphogenetic functions. These findings advance understanding of co-transcriptional regulation and highlight the significance of TF-DNA/RNA synergistic function in shaping gene regulatory networks in living organisms. |
Wednesday September 17th - Synapse and Vesicles |
| Nair, A. G., Bollmohr, N., Schokle, L., Keim, J., Melero, J. M. M., Muller, M. (2024). Presynaptic quantal size enhancement counteracts post-tetanic release depression. The Journal of physiology. PubMed ID: 39183664
Summary: Repetitive synaptic stimulation can induce different forms of synaptic plasticity but may also limit the robustness of synaptic transmission by exhausting key resources. Little is known about how synaptic transmission is stabilized after high-frequency stimulation. This study observed that tetanic stimulation of the Drosophila neuromuscular junction (NMJ) decreases quantal content, release-ready vesicle pool size and synaptic vesicle density for minutes after stimulation. This was accompanied by a pronounced increase in quantal size. Interestingly, action potential-evoked synaptic transmission remained largely unchanged. EPSC amplitude fluctuation analysis confirmed the post-tetanic increase in quantal size and the decrease in quantal content, suggesting that the quantal size increase counteracts release depression to maintain evoked transmission. The magnitude of the post-tetanic quantal size increase and release depression correlated with stimulation frequency and duration, indicating activity-dependent stabilization of synaptic transmission. The post-tetanic quantal size increase persisted after genetic ablation of the glutamate receptor subunits GluRIIA or GluRIIB, and glutamate receptor calcium permeability, as well as blockade of postsynaptic calcium channels. By contrast, it was strongly attenuated by pharmacological or presynaptic genetic perturbation of the GTPase dynamin. Similar observations were made after inhibition of the H(+)-ATPase, suggesting that the quantal size increase is presynaptically driven. Additionally, dynamin and H(+)-ATPase perturbation resulted in a post-tetanic decrease in evoked amplitudes. Finally, this study observed an increase in synaptic vesicle diameter after tetanic stimulation. Thus, a presynaptically-driven quantal size increase, likely mediated by larger synaptic vesicles, counterbalances post-tetanic release depression, thereby conferring robustness to synaptic transmission on the minute time scale. | Amado, L., Percifull, L., Franzkoch, R., Flatemersch, V., Bruggemann, E. J., Psathaki, O. E., Schuldiner, M., Bohnert, M., Bulow, M. H., Gonzalez Montoro, A. (2025). Pex3 promotes formation of peroxisome-peroxisome and peroxisome-lipid droplet contact sites. Sci Rep, 15(1):24480 PubMed ID: 40628847
Summary: Peroxisomes are ubiquitous organelles that mediate central metabolic functions, such as fatty acid β-oxidation, as well as diverse tissue- and organism-specific processes. Membrane contact sites, regions of close apposition with other organelles for direct communication, are central to several aspects of their life cycle. Pex3 is a conserved multifunctional peroxisomal transmembrane protein that is involved in the insertion of peroxisomal membrane proteins, in pexophagy, and in the formation of membrane contact sites. This study shows that high Pex3 levels in Saccharomyces cerevisiae induce the formation of peroxisome clusters surrounded by lipid droplets, mediated by peroxisome-peroxisome and peroxisome-lipid droplet contact sites. This clustering occurs independently of Pex3 partners in other processes Pex19, Inp1, and Atg36. The cytosolic domain of Pex3 binds peroxisomes, suggesting a direct role in homotypic contact site formation. Lipid droplet-peroxisome contact sites require the lipid droplet-localized triacylglycerol lipase Tgl4, which is enriched at this interface along with other lipases. Pex3 overexpression in Drosophila melanogaster similarly alters peroxisome and lipid droplet morphology and promotes contact site formation. Together, these results offer novel molecular insights into homotypic peroxisome contact sites and peroxisome-lipid droplet contact sites across species. |
| Hargitai, D., Nagy, A., Bodor, I., Szenci, G., Laczko-Dobos, H., Bhattacharjee, A., Neuhauser, N., Takats, S., Juhasz, G., Lorincz, P. (2025). HOPS-dependent vesicle tethering lock inhibits endolysosomal fusions and autophagosome secretion upon the loss of Syntaxin17. Sci Adv, 11(23):eadu9605 PubMed ID: 40479053
Summary: The autophagosomal SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein) Syntaxin17 (Syx17) plays a pivotal role in autophagosome-lysosome fusion, yet the broader impact of its loss remains elusive. Investigation of Syx17 function in Drosophila nephrocytes (spherical cells within the body cavity of the fly responsible for detoxification and clearance of unwanted substances) and salivary gland cells revealed unexpected effects. This study found that Syx17 loss induces the formation of autophagosome-lysosome clusters in a HOPS (homotypic fusion and vacuole protein sorting)-dependent manner, entrapping this tether, autophagosomes, and lysosomes. While locked in clusters, these organelles cannot participate in other vesicle fusions, impeding endosomal progression and autophagosome secretion. Therefore, the absence of Syx17 not only inhibits autophagosome-lysosome fusion but also prevents HOPS release from autophagosome-lysosome tethering sites causing a "tethering lock." Preventing autophagosome formation or removing the HOPS adaptor (pleckstrin homology domain-containing family M member 1) leads to release of HOPS and lysosomes from these clusters, thus rescuing secondary effects of Syx17 loss. These findings show that a tethering lock can disrupt multiple vesicle trafficking routes. | Gu, C., Wang, Y., Yeoman, M., Patel, B. A., Ewing, A. (2024). Subsets of Nanometer Vesicles in the Fly Release Differential Fractions of Vesicular Serotonin Content during Exocytosis. Angewandte Chemie (International ed in English):e202409783 PubMed ID: 39101881
Summary: Serotonin, a monoamine neurotransmitter, is important in both the central nervous system (CNS) and the peripheral nervous system. Malfunction of serotonin signaling leads to various disorders. Serotonin signaling from serotonergic neurons was studied inside the ventral nerve cord of Drosophila melanogaster. Serotonergic neurons and stimulated release were visualized and achieved with mCherry and channelrhodopsin-2, an optogenetically transfected ion channel, respectively, and two electrochemical techniques quantified serotonin release and vesicular content. Mean vesicular serotonin content released during exocytosis from these neurons was 84%, considerably higher than previous studies regarding octopamine (4.5%) and glutamate release (31%). Serotonin content within all vesicles is uniformly changed when serotonin concentration is inhibited or enhanced. However, serotonin release exhibits two Gaussian distributions: higher frequency of small release events, and similar or slightly higher frequency of large events, resulting in differential release fractions ranging from partial (30 to 35%) to full (100%) release after treatment with agents to either enhance or diminish release. This is the first example of consistent full exocytotic release events observed in any system. It is suggested that one pool of vesicles can release significantly diverse fractions of transmitter load during exocytosis, a potentially novel pathway to regulate exocytosis and neuronal signaling. |
| Breuer, T., Tibbe, C., Troost, T., Klein, T. (2024). Structural Analysis of the ESCRT-III Regulator Lethal(2) Giant Discs/Coiled-Coil and C2 Domain-Containing Protein 1 (Lgd/CC2D1). Cells, 13(14) PubMed ID: 39056756
Summary: Members of the LGD/CC2D1 protein family (Lethal(2)giant discs in Drosophila) contain repeats of the family-defining DM14 domains. Via this domain, they interact with members of the CHMP family (see Drosophila Shrub), which are essential for the ESCRT machinery-mediated formation of intraluminal vesicles during endosome maturation. This study investigated the requirement of the DM14 domains for the function of Lgd in detail. Although both odd-numbered DM14s can act in a functionally redundant manner, the redundancy is not complete and both contribute to the full function of Lgd. This analysis indicates that some of the AAs that form the KARRxxR motif of the on DM14s are not exchangeable by similarly charged AAs without loss of function, indicating that they not only provide charge, but also fulfil structural roles. Furthermore, this study show that the region of Lgd between DM14-4 and the C2 domain as well as its C-terminal region to the C2 domain are important for protein stability/function. Moreover, the importance of AAs that are conserved in all DM14 domains was examined. Finally, analysis of the C. elegans ortholog of Lgd revealed that it has only one DM14 domain that is functionally equivalent to the on DM14s. Altogether, the results further the understanding of how Lgd family members regulate the ESCRT machinery. | Guo, X., Zhou, J., La, Y., Liu, X., Yuan, Y., Ye, J., Zhang, Z., Chen, H., Ma, Y., Zhong, Z., Luo, G., Chen, H. (2024). Very long-chain fatty acids control peroxisome dynamics via a feedback loop in intestinal stem cells during gut regeneration. Dev Cell, 59(22):3008-3024 e3008 PubMed ID: 39047737
Summary: Peroxisome dynamics are crucial for intestinal stem cell (ISC) differentiation and gut regeneration. However, the precise mechanisms that govern peroxisome dynamics within ISCs during gut regeneration remain unknown. Using mouse colitis and Drosophila intestine models, this study has identified a negative-feedback control mechanism involving the transcription factors peroxisome proliferator-activated receptors (PPARs; see E75) and SOX21. This feedback mechanism effectively regulates peroxisome abundance during gut regeneration. Following gut injury, the released free very long-chain fatty acids (VLCFAs) increase peroxisome abundance by stimulating PPARs-PEX11s signaling. PPARs act to stimulate peroxisome fission and inhibit pexophagy. SOX21, which acts downstream of peroxisomes during ISC differentiation, induces peroxisome elimination through pexophagy while repressing PPAR expression. Hence, PPARs and SOX21 constitute a finely tuned negative-feedback loop that regulates peroxisome dynamics. These findings shed light on the complex molecular mechanisms underlying peroxisome regulation in ISCs, contributing to understanding of gut renewal and repair. |
Thursday September 11th - Disease Models |
| Buacheen, P., Karinchai, J., Inthachat, W., Butkinaree, C., Wongnoppawich, A., Imsumran, A., Temviriyanukul, P., Inoue, Y. H., Pitchakarn, P. (2025). Anoectochilus burmannicus Extract Rescues Aging-Related Phenotypes in Drosophila Susceptible to Oxidative Stress-Induced Senescence. Int J Mol Sci, 26(12) PubMed ID: 40565158
Summary: Aging is a significant risk factor for various conditions, including neurodegeneration, cardiovascular disease, and type 2 diabetes. The accumulation of reactive oxygen species (ROS) and a decline in antioxidant defense are mechanisms that are widely acknowledged as causing the acceleration of both aging and the onset of age-related diseases. To promote longevity and reduce the risk of the development of aging-related disorders, it is essential to prevent or minimize oxidative stress and enhance antioxidant defense. It has been shown that Anoectochilus burmannicus (AB), a jewel orchid rich in phenolic compounds, can impact various biological activities associated with aging prevention. These activities include antioxidant, anti-inflammation, anti-insulin resistance, and anti-obesity effects. The aim of this study was to explore whether AB extract (ABE) could serve as an anti-aging agent using a Sod1-deficient Drosophila model, which accelerates the process of aging through ROS production. The results demonstrated that ABE, at a concentration of 2.5 mg/mL, significantly extended the lifespan of the flies and helped maintain their locomotor activity as they aged. ABE also reduced the age-related accumulation of damaged proteins in the muscle of the flies by inhibiting the expression of Gstd1, a genetic marker for oxidative stress. This finding agrees with those from in vitro experiments, which have shown the potential for ABE to reduce the production of ROS induced by H2O2 in myoblasts. ABE has been shown to attenuate insulin resistance, an age-related disorder, by inhibiting the pro-inflammatory cytokine TNF-α, which in turn increased insulin-stimulated glucose uptake in adipocytes. These findings suggest a promising role of ABE as an ingredient in functional foods or nutraceuticals aimed at promoting health, preventing oxidative stress, and potentially managing age-associated diseases. | Nadiga, A. P. R., Krishna, K. L., Moin, A., Abu Lila, A. S., Danish Rizvi, S. M., Sahyadri, M., Pathak, S., Syed, S., Khafagy, E. S. (2025). Exposure of Zinc-induced Parkinson's disease-like non-motor and motor symptoms in relation to oxidative/nitrosative stress mediated neurodegeneration in the brain of Drosophila melanogaster. J Pharmacol Sci, 158(4):303-309 PubMed ID: 40543992
Summary: Parkinson's disease (PD) is the second most prevalent idiopathic neurodegenerative disorder, characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to locomotor impairment. Despite extensive research, the etiology of PD remains unclear, and existing experimental models for pharmacological evaluation do not fully replicate the disease's hallmarks, necessitating the development of a cost-effective and reliable alternative. In recent past, Drosophila melanogaster has been utilized as a model organism for various neurodegenerative diseases, including PD. The present study was conceptualized to develop a reliable PD model in the Drosophila by Zinc (Zn(+2)). Chronic exposure to 20 mM Zn(+2) for 7 days exhibited non-motor and motor PD-like symptoms in adult Drosophila flies, with reduced locomotory activity, indicating motor function deficit and reduced olfactory function and courtship behavior, indicating a deficit in non-motor function. These behavioral symptoms were associated with decreased dopamine levels. Furthermore, chronic Zn(+2) exposure resulted in enhanced membrane lipid peroxidation and decreased endogenous antioxidants level in the Drosophila brain. These effects were primarily mediated by oxidative/nitrosative stress pathway. Thus, Zn(2+)-induced PD in Drosophila serves as a cost-effective model for drug discovery, facilitating the screening of potential therapeutic compounds. Additionally, this model offers a valuable platform to investigate the molecular mechanisms underlying PD pathophysiology. |
| Liang, Y., Krivograd, A., Hofer, S. J., Kollipara, L., Zullig, T., Sickmann, A., Eisenberg, T., Sigrist, S. J. (2025). Spermidine supplementation and protein restriction protect from organismal and brain aging independently. Aging (Albany NY), 17(6):1429-1451 PubMed ID: 40489973
Summary: Brain aging and cognitive decline are significant biomedical and societal concerns. Both dietary restriction, such as limiting protein intake, and fasting, which restricts the timing of food consumption, have been proposed as strategies to delay aspects of aging. Recent studies suggest that intermittent fasting effects are mediated by the endogenous polyamine spermidine. Spermidine supplementation promotes mitochondrial integrity and functionality in aging brains by supporting hypusination of the translational initiation factor eIF5A. However, how molecular mechanisms underlying fasting mimicking interventions and protein restriction converge remain unclear, yet biomedically relevant. This study combined low- and high-protein diets (2% versus 12% yeast in food) with spermidine supplementation in aging Drosophila fruit flies. Effective hypusination was essential for normal life expectancy on both 2% and 12% yeast diets. Spermidine supplementation increased longevity, protected against age-related locomotion decline on both diets and improved memory scores in older flies regardless of protein intake. Notably, spermidine did not reduce the positive effects of the 12% protein diet on fecundity. These findings suggest that while both protein restriction and spermidine supplementation improve brain mitochondrial function, they largely operate through distinct mechanisms in modulating Drosophila brain aging. These results offer a basis for potential synergistic lifestyle interventions targeting age-related brain decline. | Ham, S. J., Bang, S., Woo, D., Jo, J. Y., Yoo, T., Yoon, E., Kyoung, Y., Baek, D., Kim, J. S., Chung, J. (2025). Mitochondrial fumarate inhibits Parkin-mediated mitophagy. Mol Cell, 85(12):2287-2302.e2289 PubMed ID: 40505663
Summary: This study explored the potential involvement of fumarate, a metabolite generated from the TCA cycle, as a key regulator of PINK1-Parkin-mediated mitophagy. Fumarate engages in a process called succination, forming S-(2-succino) cysteine with protein cysteine residues. The current research demonstrates that this modification specifically targets the sulfhydryl group of cysteine 323 and 451 residues of human Parkin, leading to the inhibition of its mitochondrial localization and E3 ligase activity, thereby impeding PINK1-Parkin-mediated mitophagy. Notably, this investigation reveals that the succinatable cysteines in human Parkin are not conserved in invertebrates, including Drosophila. To assess the functional impact of Parkin succination, Parkin knockin flies were generated with succinatable cysteines. These flies exhibit robust Parkinson's disease (PD)-related phenotypes when exposed to elevated fumarate levels. Collectively, these findings underscore the significance of fumarate as an endogenous regulator of PINK1-Parkin-mediated mitophagy, offering insights into the intricate interplay between mitochondrial metabolic activities and PD pathology. |
| 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 the phenotypes and acylcarnitine profiles of these flies were analyzed. 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 the previous identification of Mcad as the likely ACADM ortholog, and reveal the deleterious effects of a single codon deletion in Mtpα (the predicted human HADHA ortholog). Finally, 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. | Chen, E., Schmitt, J., McIntosh, G., Young, B. P., Lian, T., Liu, J., Chen, K. K., Liston, J. B., MacDonald, L., Wang, B., Medina Giro, S., Boehme, B., Das, M., Indran, S., Chao, J. T., Rogic, S., Pavlidis, P., Allan, D. W., Loewen, C. J. R. (2025). Revealing function-altering MECP2 mutations in individuals with autism spectrum disorder using yeast and Drosophila. Genetics. PubMed ID: 40546018
Summary: Pathogenic variants in MECP2 commonly lead to Rett syndrome, where MECP2's function as a DNA cytosine methylation reader is believed critical. MECP2 variants are also catalogued in individuals with autism spectrum disorder (ASD), including nine missense variants which had no known clinical significance at the start of this study. To assess these nine variants as risk alleles for ASD, MECP2 variant functional assays were developed using budding yeast and Drosophila. These assays were calibrated with known pathogenic and benign variants. The data predict that four ASD variants are loss of function and five are functional. Protein destabilization offers insight into the altered function of some of these variants. Notably, yeast and Drosophila lack DNA methylation, yet all Rett pathogenic and ASD variants located in the methyl DNA binding domain that was analyzed proved to be loss of function, suggesting a clinically-relevant role for non-methyl DNA-binding by MECP2. |
Tuesday September 9th - Physiology and metabolism |
| Knop, M., Treitz, C., Bettendorf, S., Bossen, J., von Frieling, J., Doms, S., Saboukh, A., Bruchhaus, I., Kuhnlein, R. P., Baines, J. F., Tholey, A., Roeder, T. (2025). Mitochondrial sirtuin 4 shapes the intestinal microbiota of Drosophila by controlling lysozyme expression. Anim Microbiome, 7(1):63 PubMed ID: 40514757
Summary: Sirtuins are deacetylases that are highly conserved throughout the animal kingdom. They act as metabolic sensors that coordinate cellular responses, allowing an adapted response to various stressors. Epithelial cells, especially those of the intestine, are directly exposed to a wide range of stressors. Together with the microbiota, they form a complex ecosystem with mutual influences. This study showed that a protein-restricted diet strongly increases the intestinal expression of sirtuin 4 (dSirt4), the only mitochondrial sirtuin in Drosophila. To elucidate the effects of deregulated dSirt4 expression in the intestine, dSirt4 knockout flies were analyzed. These flies showed substantial changes in their intestinal proteome and physiological properties. One of the most striking effects was the strong induction of lysozymes in the intestine, with a corresponding increase in lysozyme activity. This effect was organ-autonomous, as it was also observed in flies with dSirt4 knocked out only in intestinal enterocytes. The significant increase in lysozyme abundance in response to tissue-specific dSirt4 knockdown did not reduce the total number of bacteria in the intestine. However, it did affect the microbiota composition by reducing the number of gram-positive bacteria. This effect on microbiota composition can be attributed to dSirt4-dependent lysozyme expression, which is absent in a lysozyme-deficient background. dSirt4 knockout in the enterocytes shortened the lifespan of the flies, as did ectopic lysozyme overexpression in the enterocytes. It is concluded that the only mitochondrial sirtuin in Drosophila, dSirt4, is induced by dietary stress in intestinal epithelial cells, which directly regulates the lysozyme activity of these cells. This altered lysozyme activity was associated with a shift in the microbiota composition, demonstrating a direct link between stress, nutrition, and the host's microbiota regulation. | Kashio, S., Miura, M. (2025). S-adenosylmethionine metabolism buffering is regulated by a decrease in glycine N-methyltransferase via the nuclear ubiquitin-proteasome system.. Proc Natl Acad Sci U S A, 122(26):e2417821122 PubMed ID: 40553497
Summary: Metabolic homeostasis is essential for survival; however, many studies have focused on the fluctuations of these factors. Furthermore, while metabolic homeostasis depends on the balance between the production and consumption of metabolites, there have been limited investigations into the mechanisms regulating their consumption. S-adenosylmethionine (SAM) metabolism has diverse functions, including methylation, polyamine biosynthesis, and transsulfuration, making its regulation and control crucial. Recent studies have revealed the feedback regulation of SAM production; however, the mechanisms governing its consumption are still poorly understood. This study focused on the stability of SAM levels in the fat body (FB) of Drosophila, which serves as a functional equivalent of the mammalian liver and adipose tissue, under conditions of SAM shortage, including nutrient derprivation. Glycine N-methyltransferase (Gnmt), a major SAM-consuming methyltransferase in the FB, decreased via the nuclear ubiquitin-proteasome system (UPS), along with the inhibition of SAM synthesis and starvation. The inhibition of Gnmt level reduction by suppression of the nuclear UPS causes starvation tolerance. Thus, the regulation of Gnmt levels through nuclear UPS-mediated reduction helps maintain SAM levels under SAM shortage conditions. |
| Luo, M., Li, F., Yu, C., Guo, M., Wu, Q., Weng, Y., Wu, M., Tong, H., Yan, J. (2025). Intestinal inflammation mediates PFOA-induced sleep fragmentation and growth impairment in Drosophila. Ecotoxicol Environ Saf, 302:118541 PubMed ID: 40540892
Summary: Perfluorooctanoic acid (PFOA), a persistent synthetic perfluorinated compound with widespread environmental distribution, bioaccumulates in organisms, raising concerns about potential adverse health effects. While previous studies suggest a correlation between PFOA exposure levels and altered sleep architecture, the specific consequences of chronic PFOA exposure on sleep regulation and the underlying mechanisms remain poorly understood. Utilizing Drosophila melanogaster as a model system, this study investigated the effects of PFOA exposure. PFOA exposure resulted in significant growth inhibition, evidenced by reduced body size, and disrupted lipid metabolism. Furthermore, PFOA exposure significantly impacted sleep-wake patterns in a duration-dependent manner. Short-term exposure decreased nighttime sleep duration, whereas chronic exposure led to increased activity levels and severely fragmented sleep patterns. Mechanistically, chronic PFOA exposure significantly upregulated intestinal inflammation markers in Drosophila. Crucially, the results indicate that PFOA-induced intestinal inflammation is a key contributor to the observed sleep fragmentation. Notably, co-administration of the anti-inflammatory compound 1,8-Cineole mitigated both the intestinal inflammation and the sleep deficits caused by chronic PFOA exposure. This study elucidates a novel pathway linking chronic PFOA exposure, intestinal inflammation, and sleep disruption, providing valuable insights into the potential neurological consequences of persistent environmental pollutants. | Jin, L., Kim, C. H., Seo, J. T., Moon, S. J. (2025). Dietary salt induces taste desensitization via receptor internalization in Drosophila in a sexually dimorphic manner. Mol Cells, 48(8):100242 PubMed ID: 40541634
Summary: Sodium homeostasis, which is critical for survival, includes mechanisms for regulating salt intake that integrate central neural pathways with the peripheral taste system. Although the central homeostatic mechanisms of salt appetite are well-studied, the mechanisms by which dietary salt modulates peripheral taste responses remain unclear. This study found increased dietary salt reduces salt preference in Drosophila by desensitizing sweet gustatory receptor neurons independent of internal sodium levels. A reversible suppression was observed of salt-evoked neural responses following salt exposure accomplished via clathrin-mediated endocytosis in males and both clathrin- and C-terminal binding protein-dependent endocytosis in females. Reversing gustatory receptor neuron sexual identity switched the desensitization pattern, indicating cell-autonomous control of this sexual dimorphism. Moreover, C-terminal binding protein-mediated macropinocytosis in females also dampened sweet taste responses, revealing a sex- and modality-specific mechanism underlying sensory adaptation. These findings reveal dietary experience can affect feeding behavior by reprograming peripheral taste responses, clarifying the plasticity of nutrient sensing. |
| Millington, J. W., Lopez, J. A., Sajjadian, A. M., Scheffler, R. J., DeFelice, B. C., Ludington, W. B., Good, B. H., O'Brien, L. E., Huang, K. C. (2025). Gut microbe-derived lactic acid optimizes host energy metabolism during starvation. bioRxiv, PubMed ID: 40502158
Summary: Gut microbes convert dietary compounds into an array of metabolites that can directly provide energy to their host and indirectly impact host metabolism as systemic endocrine signals. This study shows that gut microbe-derived metabolites can extend Drosophila melanogaster survival during starvation, despite minimal alteration of dietary energy intake. Combining survival assays with mathematical modeling and untargeted metabolomics, this study identified a single, dominant mediator of starvation resilience: lactic acid produced by the commensal bacterium Lactiplantibacillus plantarum. The basis of starvation resilience is not catabolism of lactic acid using lactate dehydrogenase, but rather increased dietary energy yield through lactic acid-driven promotion of oxidative phosphorylation. These findings emphasize the role of the microbiome as a source of endocrine cues coordinating host metabolism and underscore the potential of microbiome-derived metabolites as therapeutic molecules for manipulating metabolic health and preventing disease. | Garibagaoglu, R., Kobayashi, R., Hanashiro, V., Tomita, J., Kume, K. (2025). The effect of L-alanine on sleep through taste properties in Drosophila melanogaster. Neurosci Res, 218:104924 PubMed ID: 40517958
Summary: Sleep and nutrition are important for the survival of organisms. This study focuses on the effects of amino acids, specifically L-alanine, on sleep of Drosophila melanogaster. Some amino acids including L-alanine are shown to be attractive to flies. To assess their effect on sleep, either sucrose (sweet) or sorbitol (non-sweet) was used as a base sugar of the food. Sleep was measured using monitors with infrared beams, and feeding behavior was examined by food intake and proboscis extension response tests. L-alanine supplementation in a sweet diet did not alter sleep, but supplementation in a non-sweet diet increased sleep. The addition of non-nutritive sweetener, sucralose to a non-sweet diet also increased sleep, but combining sucralose with L-alanine did not produce additive effects. L-alanine also increased the lifespan of aged flies when supplemented in a non-sweet diet. These findings suggest that the attractive taste properties of L-alanine induced sleep and offer new insights into the relationship between sleep and taste. |
Friday September 5th - Adult neural structure, development, and function |
| Kim, H. S., Santana, G. M., Sancer, G., Emonet, T., Jeanne, J. M. (2025). Divergent synaptic dynamics originate parallel pathways for computation and behavior in an olfactory circuit. Curr Biol, 35(13):3146-3162. PubMed ID: 40541186
Summary: To enable diverse sensory processing and behavior, central circuits use divergent connectivity to create parallel pathways. However, linking synaptic and cellular mechanisms to the circuit-level segregation of computation has been challenging. This study investigated the generation of parallel processing pathways in the Drosophila olfactory system, where glomerular projection neurons (PNs) diverge onto many lateral horn neurons (LHNs). The effects of a single PN's activity on two of its target LHNs were compared. One LHN type generates sustained responses to odor and adapts divisively. The other generates transient responses and adapts subtractively. The distinct odor-coding dynamics originate from differences in the dynamics of PN synapses targeting each LHN type. Sustained LHN responses arise from synapses that recover from depression quickly enough to maintain ongoing transmission. Divisive adaptation is due to slow cellular gain control implemented by the Na(+)/K(+) ATPase in the postsynaptic neuron. Transient LHN responses arise from synapses that recover from depression too slowly to maintain ongoing transmission but that also facilitate when PN spike rate increases. Interfering with facilitation via the calcium buffer EGTA or interfering with the presynaptic priming factor "Unc13B diminishes the magnitude of initial transient responses. Subtractive adaptation is due to the nonlinearity imposed by the spike threshold in the postsynaptic neuron. Transient LHNs make corresponding transient contributions to behavioral odor attraction in walking flies, whereas sustained LHNs may make sustained, but nuanced, contributions. Subcellular presynaptic specialization is thus a compact and efficient way to originate parallel information streams for specialized computation and behavior. | Huertas Radi, M., Corke, J., Baines, R. A. (2025). Seizure Activity Induced by Electroshock in Drosophila Larvae. J Vis Exp, (220) PubMed ID: 40549583
Summary: Epilepsy presents a significant health burden that is exacerbated by high numbers of individuals who are drug-refractory. Whilst some drug-refractory patients do respond to non-drug treatments (e.g., vagal nerve stimulation, ketogenic diet, etc.), the last resort for many is challenging and expensive surgery to provide relief from seizures. Whilst it is generally acknowledged that antiseizure medications with a broader range of targets are required, the hurdle in achieving this is the identification of novel drug targets. Genetically tractable model animals offer promise in this regard. The fruit fly, Drosophila melanogaster, has become a powerful model for investigating the mechanistic basis of, and better treatments for, seizures. Many identified fly mutations result in larvae and adults exhibiting seizure-like activity in response to strong stimulation (electrical, mechanical, and/or thermal). Many of these mutations are in genes homologous to those that contribute to human genetic epilepsies (e.g., the voltage-gated Na(+) channel). It is also now possible to replace a fly gene with its human equivalent that additionally, carries a disease-related mutation. Thus, the humble fly has become an avatar to model human disease. This study describes a suitable method to use Drosophila larvae for low to medium-throughput drug screens to identify unique compounds, and their targets, that have antiseizure potential. |
| Miao, H., Kim, W. J. (2025). Electrical silencing of dendritic arborization neurons rescues toxic polyglutamine-induced locomotion defect. Fly (Austin), 19(1):2519687 PubMed ID: 40519063
Summary: This study investigates the effects of polyglutamine (polyQ) expansions on the locomotion of Drosophila larvae, focusing on the role of class IV dendritic arborization (da) neurons. PolyQ expansions are associated with neurodegenerative diseases like Huntington's disease, and Drosophila is a valuable model organism for studying these diseases due to its genetic tractability and short generation time. Expressing a polyQ protein in class IV da neurons caused significant locomotion deficits. Specifically, larvae with polyQ expression exhibited slower crawling speed and increased turn frequency, indicating impaired movement. The most intriguing finding of this study was that electrically silencing class IV da neurons completely rescued the locomotion deficits caused by polyQ expression. By expressing a potassium channel that makes the neurons less active, the locomotion defects were effectively reversed. This suggests that modulating the activity of these neurons could be a promising therapeutic approach for treating polyQ diseases. These findings have significant implications for understanding polyQ diseases and developing new therapeutic approaches. By electrically silencing these neurons, the harmful effects of polyQ-induced cation channels, which are thought to disrupt cellular function, may be prevente. This opens up exciting possibilities for exploring electrical silencing as a potential treatment for polyQ diseases, offering hope for future therapies that target the underlying mechanisms of these devastating conditions. | Hardin, K. R., Penas, A. B., Joubert, S., Ye, C., Myers, K. R., Zheng, J. Q. (2025). A critical role for the Fascin family of actin bundling proteins in axon development, brain wiring and function. Mol Cell Neurosci:104027 PubMed ID: 40553926
Summary: Actin-based cell motility drives many neurodevelopmental events including guided axonal growth. Fascin is a major family of F-actin bundling proteins, but its role in axon development in vivo and brain wiring remains unclear. This study reports that fascin is required for axon development, brain wiring and function. This study shows that fascin is enriched in the motile filopodia of axonal growth cones and its inhibition impairs axonal extension and branching of hippocampal neurons in culture. Evidence is provided that fascin is essential for axon development and brain wiring in vivo using Drosophila melanogaster as a model. Drosophila expresses a single ortholog of mammalian fascin called Singed (SN), which is expressed in the mushroom body (MB) of the central nervous system. Loss of SN causes severe MB disruption, marked by α- and β-lobe defects indicative of altered axonal guidance. SN-null flies also exhibit defective sensorimotor behaviors as assessed by the negative geotaxis assay. MB-specific expression of SN in SN-null flies rescues MB structure and sensorimotor deficits, indicating that SN functions autonomously in MB neurons. Together, these data from primary neuronal culture and in vivo models highlight a critical role for fascin in brain development and function. |
| Lesser, E., Moussa, A., Tuthill, J. C. (2025). Peripheral anatomy and central connectivity of proprioceptive sensory neurons in the Drosophila wing. bioRxiv, PubMed ID: 40501889
Summary: Recent advances in electron microscopy (EM) and automated image segmentation have produced synaptic wiring diagrams of the Drosophila central nervous system. A limitation of existing fly connectome datasets is that most sensory neurons are excised during sample preparation, creating a gap between the central and peripheral nervous systems. This gap was bridged by reconstructing wing sensory axons from the Female Adult Nerve Cord (FANC) EM dataset and mapping them to peripheral sensory structures using genetic tools and light microscopy. The location and identity of known wing mechanosensory neurons was confirmed and previously uncharacterized axons, including a novel population of putative proprioceptors that make monosynaptic connections onto wing steering motor neurons were identified. This study also found that proprioceptors of adjacent campaniform sensilla on the wing have distinct axon morphologies and postsynaptic partners, suggesting a high degree of specialization in axon pathfinding and synaptic partner matching. The peripheral location and central projections of wing sensory neurons are stereotyped across flies, allowing this wing proprioceptor atlas and genetic toolkit to guide analysis of other fly connectome datasets. | Huang, N., Zhou, J., Gao, Y., Peng, Y., Hu, W., Ou, G., Li, Q., Zhong, Y. (2025). Rapid memory shift between different synaptic ensembles promotes forgetting in Drosophila. Curr Biol, 35(13):3119-3132. PubMed ID: 40513570
Summary: Forgetting is increasingly recognized as an active adaptive process, yet its mechanism remains elusive at the cellular and synaptic levels. This study show sthat the natural decay of hours-scale memory in Drosophila is promoted through shifting memory traces between distinct synaptic ensembles. Aversive conditioning produces an initial memory trace of presynaptic depression primarily confined to the γ1 compartment, one of five axonal compartments of γ Kenyon cells, that drives avoidance behavior. The memory trace later is shifted to the γ4 compartment, but is encoded as presynaptic potentiation. This shift is initiated by Rac1/Dia activation, which rapidly adds active zones (AZs), followed by Ephrin-dependent AZ elimination in the γ4 compartment, promoting decay. Preventing this shift preserves γ1 memory trace for over 1 day without forgetting. Thus, forgetting is achieved by shifting memory trace from early, more persistent presynaptic depression to new synaptic ensemble-encoded presynaptic potentiation prone to accelerated memory decay. |
Tuesday September 2nd - Evolution |
| Fan, T., Cridland, J. M., Begun, D. J. (2025). Adaptive gene expression parallelism in the male reproductive tract of two Drosophila species. Genetics, PubMed ID: 40492850
Summary: While stabilizing selection is likely an important process leading to conserved phylogenetic patterns of gene expression, the role of selection in driving expression divergence amongst populations and species is much less clear. One approach for identifying adaptation is to document parallel evolution, the independent evolution of similar phenotypes in multiple species in response to similar selective pressures. Latitudinal clines are a classic system for studying adaptation in many species, including Drosophila; multiple species exhibit clines for several phenotypes, such as body and wing size. However, the extent of latitudinal transcriptome variation and the degree to which such variation is shaped by selection remain unclear. This study investigated transcriptomes of North American D. melanogaster and D. simulans with a focus on the male reproductive tract. For both species accessory glands and testis were sampled from lines derived from two locations, one low latitude (Panama City, Panama), and one high latitude (Maine, USA). A striking similarity between species was observed in the directionality and magnitude of latitudinal expression variation in the accessory gland but not in the testis. This suggests that selection has fine-tuned accessory gland transcript abundance in a similar manner in response to latitudinal selection pressures in both species. In addition to gene level parallelism, these species exhibit correlated fluctuations of high vs. low latitude expression differences on a larger chromosomal scale. Analysis of whole male transcriptomes from the same population samples suggests that parallel latitudinal selection responses play an important role in expression adaptation for both species. | Crowley-Gall, A., Layne, J. E., Ammagarahalli, B., Hamrick, A. A., Lawson, L. P., Rollmann, S. M. (2025). Olfactory variation among closely related cactophilic Drosophila species.J Comp Physiol A Neuroethol Sens Neural Behav Physiol, PubMed ID: 40504427
Summary: Chemosensation plays an important role in a wide range of behaviors including host identification and localization, oviposition site selection, and mate recognition. Variation in the ability to detect chemical signals may influence behavior in animals like insects that use volatile cues emitted from plants when discriminating between potential hosts. Differences in has been demonstrated to play a crucial role in driving changes in host use within and between insect species, leading to reproductive isolation between populations and eventual speciation through specialized host adaptation. Between-species variation in odor tuning was examined, and whether variation is linked to shifts in host plant use was examined in the Drosophila repleta species group, a taxonomic radiation of flies specializing on cacti that exhibits multiple shifts in host plant use across their phylogeny resulting in three current states: (1) Opuntia cactus specialists, (2) columnar cactus specialists, and (3) cactus "generalists" which use both hosts. Odor response profiles were measured from select olfactory sensillar subtypes across multiple species within the group as well as for the outgroup D. melanogaster. Variation in both sensitivity and specificity to odors was observed, with some olfactory sensory neurons exhibiting differences associated with host cactus use. This study is the first in-depth analysis of the olfactory system across the repleta species group and provides the opportunity to test for conserved mechanisms in the olfactory system underlying divergence and host shift. |
| Forsberg, S. K. G., Melo, D., Wolf, S. W., Grenier, J. K., Tang, M., Henry, L. P., Pallares, L. F., Clark, A. G., Ayroles, J. F. (2025). Longitudinal sequencing reveals polygenic and epistatic nature of genomic response to selection. Proc Natl Acad Sci U S A, 122(25):e2410452122 PubMed ID: 40531879
Summary: Evolutionary adaptation to new environments likely results from a combination of selective sweeps and polygenic shifts, depending on the genetic architecture of traits under selection. While selective sweeps have been widely studied, polygenic responses are thought to be more prevalent but remain challenging to quantify. The infinitesimal model makes explicit the hypothesis about the dynamics of changes in allele frequencies under selection, where only allelic effect sizes, frequencies, linkage, and gametic disequilibrium matter. Departures from this, like long-range correlations of allele frequency changes, could be a signal of epistasis in polygenic response. An Evolve & Resequence experiment was performed in Drosophila melanogaster exposing flies to a high-sugar diet for over 100 generations. Allele frequency changes were tracked in >3000 individually sequenced flies and population pools, and loci under selection were sought by identifying sites with allele frequency trajectories that differentiated selection regimes consistently across replicates. It was estimated that at least 4% of the genome was under positive selection, indicating a highly polygenic response. The response was dominated by small, consistent allele frequency changes, with few loci exhibiting large shifts. Signatures of selection on pairwise combinations of alleles were sought in the new environment and found several strong signals of putative epistatic interactions across unlinked loci that were consistent across selected populations. Finally,differentially expressed genes (DEGs) were measured across treatments; DEGs were shown to be enriched for selected SNPs. These results suggest that epistatic contributions to polygenic selective response are common and lead to detectable signatures. | Merayo, M., Delgado, K. M., Salguero, D., Orengo, D. J. (2025). Chromosomal Inversions in Chromosome U of Drosophila subobscura: A Story from Population Studies to Molecular Level. Insects, 16(6) PubMed ID: 40559016
Summary: Drosophila subobscura is a Palearctic species that colonized the west coast of South and North America in the last quarter of the 20th century. This species stands out for its large chromosomal inversion polymorphism that affects its five long chromosomes. Studies of natural populations revealed that the inversion polymorphism has an adaptive character and while the arrangement U(st) was classified as adapted to cold, other arrangements, such as U(1+2+6) and U(1+8)(+2), were considered warm adapted. Characterization of the inversion breakpoints will allow a first approach to the genes included in the inversions and to find candidates to be affected by selection. In this work, advantage was taken of the existence of a reference genomic sequence carrying the U(1+2) arrangement to locate the breakpoints of the U(6) and U(8) inversions, mapping paired-end Illumina reads from two homokaryotypic strains to U(1+2+6) and U(1+8)(+2), respectively. To date, most of the characterized inversion breakpoints in D. subobscura have been generated by non-homologous end-joining. In contrast, the U(6) and U(8) inversions seem to have originated by transposons, and, at the distal breakpoint of inversion U(8), a new fold-back-like element characteristic of the suboscura species group is described that was named Ziga-Zaga. |
| McDonald, G. C., Edmunds, D., Morimoto, J., Wigby, S., Perry, J. C. (2025). A male-biased sex ratio increases the opportunity for precopulatory sexual selection but does not change the Bateman gradient. Evol Lett, 9(3):324-334 PubMed ID: 40487865
Summary: Theory predicts that the sex ratio within populations should influence the strength of sexual selection, and sex ratio is often used as a proxy for sexual selection. However, recent studies challenge this relationship. This study manipulated adult sex ratios in Drosophila melanogaster to comprehensively investigate the relationship between sex ratio and sexual selection. Consistent with theory, stronger sexual selection was found in males than females and an increased variance in male reproductive success (the opportunity for selection) in male-biased sex ratios. In addition, males faced more intense sperm competition in male-biased sex ratios, although the structure of sexual networks was largely invariant to sex ratio. Despite this, sex ratios did not influence sexual selection in males as measured by the Bateman gradient. Randomized null models were leveraged to reconcile these results and show that the higher male reproductive variance in male-biased sex ratios may be explained by random chance in mating, rather than competitive mechanisms. These findings indicate that caution is warranted over the long-standing assumption that sex ratio bias is a good proxy for the strength of sexual selection. | Kendrick, C., Agrawal, A. F., Rundle, H. D. (2025). Local Adaptation of Male Sexual Fitness in Drosophila melanogaster. Evolution, PubMed ID: 40493447
Summary: Mate competition gives rise to sexual selection, and healthier, more vigorous males are likely to be superior competitors. Because most genes are likely to impact an individual's vigor, sexual selection should act across much of the genome to favor the same alleles as natural selection, thereby promoting adaptation. On the other side of the coin, adaptation to an environment should enhance male sexual fitness in that environment because it is likely to increase the overall vigor of individuals within a population. Surprisingly, there are few tests of this latter prediction and results are mixed. Taking advantage of a long-term evolution experiment involving replicate populations of Drosophila melanogaster, a reciprocal transplant was performed in which the sexual fitness of males was compared when raised in an environment to which they were well adapted and in one to which they were not. Male sexual fitness was a comprehensive measure that included pre- and post-copulatory reproductive success in a competitive assay performed under conditions that closely mirrored those to which the populations had been evolving. The results add support to the idea that local adaptation to the abiotic environment enhances male sexual fitness. |
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