What's hot today: Current papers in developmental biology and gene function

What's hot today:
Current papers in developmental biology and gene function

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Monday September 21st - Evolution

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Edwards, S., Naundrup, A., Becher, P. G., De Fine Licht, H. H. (2025). Patterns of genotype-specific interactions in an obligate host-specific insect pathogenic fungus. J Evol Biol, 38(2):225-239 PubMed ID: 39671697
Summary:
Host-pathogen infections and possible effects on co-evolutionary patterns depend on the genotypes of both host and pathogen. Obligate fungal pathogens of plants are often characterized by host-pathogen genotype-by-genotype (GxG) interactions, but whether these patterns exist in obligate insect fungal pathogens is unclear. This study took advantage of the obligate insect pathogenic fungus Entomophthora muscae, where individual isolates are specific to different dipteran host species in nature but can cross-infect multiple fly species in the laboratory. Three new isolates of E. muscae were collected from Drosophila species. Phylogenetic analysis showed that Drosophila-isolated E. muscae represents a distinct geographically widespread Drosophila lineage compared to the house fly (Musca domestica) or Delia species-isolated E. muscae. The three new E. muscae isolates from Drosophila spp. were used together with a genetically distinct E. muscae isolate from house flies, and their virulence was assessed in a cross-infection experiment using one house fly, three Drosophila suzukii, and two D. melanogaster genotypes as hosts. All fungal isolates successfully infected hosts, induced behavioural manipulation, sporulated in all fly hosts, and differed in virulence between host genotypes, revealing GxG interactions. While house flies were most susceptible to fungal infection with 99% mortality, a lower virulence of 49% and 25% mortality was found in D. melanogaster and D. suzukii genotypes, respectively. Furthermore, all isolates harboured a specific mycovirus (family Iflaviridae), but co-phylogenetic branching patterns did not support fungus-virus co-speciation. This study has shown that the genetic makeup of both fungal pathogen and fly host influence E. muscae infectivity, confirming GxG interactions in obligate fly fungal pathogens.

Jezovit, J. A., Levine, J. D. (2025). Chemical signals and social structures strengthen sexual isolation in Drosophila pseudoobscura. Communications biology, 8(1):76 PubMed ID: 39824898
Summary:
Species that coexist in hybrid zones sexually isolate through reproductive character displacement, a mechanism that favours divergence between species. In Drosophila, behavioural and physiological traits discourage heterospecific mating between species. Recently, social network analysis revealed flies produce strain-specific and species-specific social structures. A gene, degrees of kevin bacon (dokb) has also been discovered that accounts for differences in social structures between flies. Why differences in social structures exist between drosophilids is currently unknown. This study shows through an experimental evolution study that six generations of selection in experimental sympatry led to the divergence of social structures measured in Drosophila pseudoobscura and Drosophila persimilis flies. The frequency of hybrid offspring decreased within a few generations, suggesting social structures are associated with the sexual isolation of species. This study also reports increased species' differences in the concentration of the cuticular hydrocarbon 5, 9-pentacosadiene after six generations of selection. The mean concentration of this compound converged in female flies of both species and diverged in male flies of both species, suggesting a quantitative link between increased sexual dimorphism and sexual isolation. These results suggest that chemical signals, together with social structures, increase the sexual isolation between species in hybrid zones.

Cherezov, R. O., Vorontsova, J. E., Kuvaeva, E. E., Akishina, A. A., Zavoloka, E. L., Simonova, O. B. (2025). The lawc gene emerged de novo from conserved genomic elements and acquired a broad expression pattern in Drosophila. J Genet Genomics, 52(7):901-914 PubMed ID: 39733859
Summary:
It has recently become evident that the de novo emergence of genes is widespread and documented for a variety of organisms. De novo genes frequently emerge in proximity to existing genes, forming gene overlaps. This study presents an analysis of the evolutionary history of a putative de novo gene, lawc, which overlaps with the conserved Trf2 gene, which encodes a general transcription factor in Drosophila melanogaster. lawc emerged approximately 68 million years ago in the 5'-untranslated region (UTR) of Trf2 and displays an extensive spatiotemporal expression pattern. One of the most remarkable features of the lawc evolutionary history is that its emergence was facilitated by the engagement of Drosophilidae-specific short, highly conserved regions located in Trf2 introns. This represents a unique example of putative de novo gene birth involving conserved DNA regions localized in introns of conserved genes. The observed lawc expression pattern may be due to the overlap of lawc with the 5'-UTR of Trf2. This study not only enriches understanding of gene evolution but also highlights the complex interplay between genetic conservation and innovation.

Jean-Francois, F., Pratibha, S., Baptiste, R., Jean-Pierre, F., Jerome, C., Deepa, A., Claude, E. (2025). Is Drosophila Larval Competition Involved in Incipient Speciation? J Chem Ecol, 51(1):2 PubMed ID: 39841299
Summary:
Geographical, ethological, temporal and ecological barriers can affect interbreeding between populations deriving from an ancestral population, this progressively leading to speciation. A rare case of incipient speciation currently occurs between Drosophila melanogaster populations sampled in Zimbabwe (Z) and all other populations (M). This phenomenon was initially characterized by Z females refusing to mate with M males. Despite the fact that Z and M flies produce different amounts of cuticular pheromones, their manipulation and that of other sensory signals exchanged during courtship behavior only marginally rescued the behavioral isolation. To further explore the putative mechanisms involved in this phenomenon, the fecundity in matings between Z and M flies was assessed. Then, the reproduction and survival in adults resulting of co-cultured Z and M larvae was measured. In these two experiments, Z flies rarely emerged. Z and M larvae produced different amounts of food-derived metabolites which were altered in co-culture condition. This maybe related to the different bacteria composition in the gut and body of Z and M flies. However, the mating behavior of co-cultured flies did not change and their cuticular pheromone profile was slightly altered. Thus, the Z/M larval competition could reinforce the barriers induced by gametic and behavioral isolation processes on this incipient speciation phenomenon.

Jarvis, W. M. C., Careau, V., Rundle, H. D. (2025). Divergence in genetic (co)variances and the alignment of gmax with phenotypic divergence. Evolution; international journal of organic evolution, 79(4):597-610 PubMed ID: 39841166
Summary:
To better understand the sources of biological diversity in nature, information is needed on the mechanisms underlying population divergence. Biological systems with patterns of naturally occurring adaptive variation among populations can provide insight into the genetic architecture of diverging traits and the influence of genetic constraints on responses to selection. Using a system of reproductive character displacement in the North American mushroom-feeding fly Drosophila subquinaria, this study assessed patterns of genetic (co)variance among a suite of chemical signaling traits and divergence in this pattern among populations. D. subquinaria exhibits stronger reproductive isolation against the closely related Drosophila recens in sympatry, where both female mating preferences and male chemical signaling traits have diverged from the ancestral allopatric populations. Three wild populations were collected from each region and, in the lab, the phenotypic divergence in these traits were characterized, as well as the additive genetic (co)variance structure (G-matrix), via replicate breeding designs. Divergence was found between allopatric and sympatric D. subquinaria in the shape and size of the G-matrix, and the leading axis of genetic variance (gmax) had changed in sympatry to come into alignment with the primary axis of phenotypic divergence between the sympatric and allopatric regions.

Rohner, P. T., Berger, D. (2025). Macroevolution along developmental lines of least resistance in fly wings. Nat Ecol Evol, 9(4):639-651 PubMed ID: 39920350
Summary:
Evolutionary change requires genetic variation, and a reigning paradigm in biology is that rates of microevolution can be predicted from estimates of available genetic variation within populations. However, the accuracy of such predictions should decay on longer evolutionary timescales, as the influence of genetic constraints diminishes. This study shows that intrinsic developmental variability and standing genetic variation in wing shape in two distantly related flies, Drosophila melanogaster and Sepsis punctum, are aligned and predict deep divergence in the dipteran phylogeny, spanning >900 taxa and 185 million years. This alignment cannot be easily explained by constraint hypotheses unless most of the quantified standing genetic variation is associated with deleterious side effects and is effectively unusable for evolution. However, phenotyping of 71 genetic lines of S. punctum revealed no covariation between wing shape and fitness, lending no support to this hypothesis. Little evidence was found for genetic constraints on the pace of wing shape evolution along the dipteran phylogeny. Instead, correlational selection related to allometric scaling, simultaneously shaping developmental variability and deep divergence in fly wings, emerges as a potential explanation for the observed alignment. This suggests that pervasive natural selection has the potential to shape developmental architectures of some morphological characters such that their intrinsic variability predicts their long-term evolution.

Friday September 18th - Adult physiology and Metabolism

Yadav, S., Pan, X., Li, S., Martin, P. L., Hoang, N., Chen, K., Karhadkar, A., Malhotra, J., Zuckerman, A. L., Munan, S., Klose, M. K., Wang, L., Cracan, V., Parkhitko, A. A. (2025). Tissue-specific modulation of NADH consumption as an anti-aging intervention in Drosophila. JbioRxiv, PubMed ID: 39829793
Summary:
Aging is characterized by extensive metabolic dysregulation. Redox coenzyme nicotinamide adenine dinucleotide (NAD) can exist in oxidized (NAD(+)) or reduced (NADH) states, which together form a key NADH/NAD(+) redox pair. Total levels of NAD decline with age in a tissue-specific manner, thereby playing a significant role in the aging process. Supplementation with NAD precursors boosts total cellular NAD levels and provides some therapeutic benefits in human clinical trials. However, supplementation studies cannot determine tissue-specific effects of an altered NADH/NAD(+) ratio. This study created transgenic Drosophila expressing a genetically encoded xenotopic tool LbNOX to directly manipulate the cellular NADH/NAD(+) ratio. LbNOX expression in Drosophila was shown to impact both NAD(H) and NADP(H) metabolites in a sex-specific manner. LbNOX rescues neuronal cell death induced by the expression of mutated alpha-B crystallin in the Drosophila eye, a widely used system to study reductive stress. Utilizing LbNOX, targeting redox NAD metabolism in different tissues may have drastically different outcomes, as the expression of LbNOX solely in the muscle is much more effective for rescuing paraquat-induced oxidative stress compared to whole-body expression. Excitingly, we demonstrate that perturbing NAD(P) metabolism in non-neuronal tissues is sufficient to rejuvenate sleep profiles in aged flies to a youthful state. In summary, the xenotopic tool LbNOX was used to identify tissues and metabolic processes which benefited the most from the modulation of the NAD metabolism thereby highlighting important aspects of rebalancing the NAD and NADP pools, all of which can be translated into novel designs of NAD-related human clinical trials.

Alaraby, M., Abass, D., Gutierrez, J., Velazquez, A., Hernandez, A., Marcos, R. (2024). Reproductive Toxicity of Nanomaterials Using Silver Nanoparticles and Drosophila as Models. Molecules, 29(23) PubMed ID: 39683959
Summary:
Reproductive toxicity is of special concern among the harmful effects induced by environmental pollutants; consequently, further studies on such a topic are required. To avoid the use of mammalians, lower eukaryotes like Drosophila are viable alternatives. This study addresses the gap in understanding the link between reproductive adverse outcomes and the presence of pollutants in reproductive organs by using Drosophila. Silver nanoparticles (AgNPs) were selected for their ease of internalization, detection, and widespread environmental presence. Both male and female flies were exposed to AgNPs for one week. Internalization and bioaccumulation of AgNPs in organs were assessed using transmission electron microscopy, confocal microscopy, and inductively coupled plasma mass spectrometry. Substantial accumulation of AgNPs in the gastrointestinal tract, Malpighian tubules, hemolymph, reproductive organs (ovaries and testes), and gametes were observed. The highest AgNP content was observed in testes. Exposure to AgNPs reduced ovary size and fecundity, though fertility and gender ratios of the offspring were unaffected. Significant deregulation of reproductive-related genes was observed, particularly in males. These findings underscore the utility of Drosophila as a model for evaluating reproductive hazards posed by AgNP exposure. The ease of AgNP internalization in Drosophila reproductive targets could be extrapolated to mammalians, raising concerns about the potential impacts of nanoparticle exposure on reproduction toxicity in humans.

Bettinazzi, S., Liang, J., Rodriguez, E., Bonneau, M., Holt, R., Whitehead, B., Dowling, D. K., Lane, N., Camus, M. F. (2024). Assessing the role of mitonuclear interactions on mitochondrial function and organismal fitness in natural Drosophila populations. Evol Lett, 8(6):916-926 PubMed ID: 39677574
Summary:
Mitochondrial function depends on the effective interactions between proteins and RNA encoded by the mitochondrial and nuclear genomes. Evidence suggests that both genomes respond to thermal selection and promote adaptation. However, the contribution of their epistatic interactions to life history phenotypes in the wild remains elusive. This study investigated the evolutionary implications of mitonuclear interactions in a real-world scenario that sees populations adapted to different environments, altering their geographical distribution while experiencing flow and admixture. A Drosophila melanogaster panel was created with replicate native populations from the ends of the Australian east-coast cline, into which the mtDNA haplotypes were substituted that were either predominant or rare at each cline-end, thus creating putatively mitonuclear matched and mismatched populations. The results suggest that mismatching may impact phenotype, with populations harboring the rarer mtDNA haplotype suffering a trade-off between aerobic capacity and key fitness aspects such as reproduction, growth, and survival. The significance of mitonuclear interactions as modulators of life history phenotypes is discussed in the context of future adaptation and population persistence.

Wu, S. C., Chen, Y. J., Su, S. H., Fang, P. H., Liu, R. W., Tsai, H. Y., Chang, Y. J., Li, H. H., Li, J. C., Chen, C. H. (2025). Dysfunctional BCAA degradation triggers neuronal damage through disrupted AMPK-mitochondrial axis due to enhanced PP2Ac interaction. Communications biology, 8(1):105 PubMed ID: 39838082
Summary:
Metabolic and neurological disorders commonly display dysfunctional branched-chain amino acid (BCAA) metabolism, though it is poorly understood how this leads to neurological damage. This was investigated by generating Drosophila mutants lacking BCAA-catabolic activity, resulting in elevated BCAA levels and neurological dysfunction, mimicking disease-relevant symptoms. The findings reveal a reduction in neuronal AMP-activated protein kinase (AMPK) activity, which disrupts autophagy in mutant brain tissues, linking BCAA imbalance to brain dysfunction. Mechanistically,excess BCAA-induced mitochondrial reactive oxygen species (ROS) was shown to trigger the binding of protein phosphatase 2 A catalytic subunit (PP2Ac) to AMPK, suppressing AMPK activity. This initiated a dysregulated feedback loop of AMPK-mitochondrial interactions, exacerbating mitochondrial dysfunction and oxidative neuronal damage. This study identifies BCAA imbalance as a critical driver of neuronal damage through AMPK suppression and autophagy dysfunction, offering insights into metabolic-neuronal interactions in neurological diseases and potential therapeutic targets for BCAA-related neurological conditions.

Wang, F., Yang, P., Xu, L., Han, X., Zhang, M. (2025). Effects of cadmium on female Drosophila melanogaster and its transgenerational inheritance effects. J Environ Manage, 374:124076 PubMed ID: 39818074
Summary:
Cadmium (Cd) is a silvery-white and shiny heavy metal that is common in daily life and can adversely affect the development, lifespan, and reproduction of organisms. In this study, Drosophila melanogaster (F(0)) were cultured from eggs to adults in medium containing different Cd concentrations (0, 2.25, and 4.5 mg/kg), and offspring (F(1)-F(4) generations) were cultured in standard medium. The morphology of the ovaries of female flies under Cd stress changed, apoptosis occurred, fertility decreased, and the levels of 20-Hydroxyecdysone and vitellogenin decreased significantly. These changes were more significant under high-concentration treatment. In addition, the inhibitory effects of Cd on reproduction-related genes (spook, phantom, disembodies, shadow, shade, ECR, vg, and Kr-h1) in F(0) female flies could transmit to two or three generations. Cd exposure also induced increased expression of miR-927 and mediated its transgenerational inheritance. These results indicate that damage to the ovaries and the changes in related-genes expressions of female flies induced by Cd stress can be transmitted to offspring and may be related to changes in miRNA expression in Drosophila. The transgenerational inheritance effects of heavy metals on organisms and their potential risks to future ecosystems deserve attention and reassess.

Benedetti, L., Fan, R., Weigel, A. V., Moore, A. S., Houlihan, P. R., Kittisopikul, M., Park, G., Petruncio, A., Hubbard, P. M., Pang, S., Xu, C. S., Hess, H. F., Saalfeld, S., Rangaraju, V., Clapham, D. E., De Camilli, P., Ryan, T. A., Lippincott-Schwartz, J. (2025). Periodic ER-plasma membrane junctions support long-range Ca(2+) signal integration in dendrites. Cell, 188(2):484-500.e422 PubMed ID: 39708809
Summary:
Neuronal dendrites must relay synaptic inputs over long distances, but the mechanisms by which activity-evoked intracellular signals propagate over macroscopic distances remain unclear. This study discovered a system of periodically arranged endoplasmic reticulum-plasma membrane (ER-PM) junctions tiling the plasma membrane of dendrites at ~1 μm intervals, interlinked by a meshwork of ER tubules patterned in a ladder-like array. Populated with Junctophilin-linked plasma membrane voltage-gated Ca(2+) channels and ER Ca(2+)-release channels (ryanodine receptors), ER-PM junctions are hubs for ER-PM crosstalk, fine-tuning of Ca(2+) homeostasis, and local activation of the Ca(2+)/calmodulin-dependent protein kinase II. Local spine stimulation activates the Ca(2+) modulatory machinery, facilitating signal transmission and ryanodine-receptor-dependent Ca(2+) release at ER-PM junctions over 20 μm away. Thus, interconnected ER-PM junctions support signal propagation and Ca(2+) release from the spine-adjacent ER. The capacity of this subcellular architecture to modify both local and distant membrane-proximal biochemistry potentially contributes to dendritic computations.

Wednesday September 16th - Signaling

Kinoshita, J., Kinoshita, Y., Nomura, T., Inoue, Y. H. (2024). Macrophage-like Blood Cells Are Involved in Inter-Tissue Communication to Activate JAK/STAT Signaling, Inducing Antitumor Turandot Proteins in Drosophila Fat Body via the TNF-JNK Pathway. Int J Mol Sci, 25(23) PubMed ID: 39684820
Summary:
Turandot (Tot) family proteins (consisting of 8 members), which are induced via the JAK/STAT pathway after infection, also suppress lymph gland tumors in Drosophila mxc(mbn1) mutant larvae. The potential role of hemocytes (immune blood cells) in Tot induction in tumor-bearing mutants was examined via immunostaining and RNAi experiments. Normal hemocytes transplanted into mutant larvae were recruited to the tumor and fat body (FB), suggesting that these cells transmit tumor-related information. The transplanted hemocytes ectopically expressed Unpaired3 (Upd3), which is necessary for the activation of JAK/STAT. Eiger, a Drosophila tumor necrosis factor (TNF) ortholog, was highly expressed in tumors. Depletion of the Eiger receptor in hemocytes reduced Tot levels and eventually enhanced tumor growth. The c-Jun N-terminal kinase (JNK) pathway, acting downstream of the receptor, was also activated in the hemocytes of mutants. Downregulation of the JNK pathway in hemocytes inhibited Tot induction, leading to enhanced tumor growth. These results suggest that upd3 expression in hemocytes depends on the Eiger-JNK pathway. It is proposed that after Eiger activates the JNK pathway in hemocytes present on the tumor, cells expressing Upd3 are recruited to the FB. Upd3 then activates JAK/STAT to induce the expression of antitumor proteins. This study highlights the intricate communication between tissues via blood cells during tumor suppression.

Garcia-Alonso, L. (2024). Fasciclin 2 functions as an expression-level switch on EGFR to control organ shape and size in Drosophila. PLoS One, 19(12):e0309891 PubMed ID: 39705210
Summary:
Fasciclin 2 (Drosophila NCAM) is a homophilic Cell Adhesion Molecule expressed at moderate levels in the proliferating epithelial cells of imaginal discs, where it engages EGFR in a cell autonomous auto-stimulatory loop that promotes growth along larval development. In addition, Fasciclin 2 is expressed at high levels in the pre-differentiating cells of imaginal discs. Gain-of-function genetic analysis shows that Fasciclin 2 acts as a non-cell autonomous repressor of EGFR when high expression levels are induced during imaginal disc growth. Loss-of-function genetic analysis shows that this Fasciclin 2 functional facet is required at the end of larval development and it is mediated by interaction with IgCAMs CG15630 (Fipi) and CG33543 (Elff). Thus, Fasciclin 2 bears two complementary functional roles which correspond with different levels of expression. The combined results from loss- and gain-of-function analyses suggest a scenario where the Fasciclin 2/EGFR cell autonomous auto-stimulatory loop promotes cell proliferation until reaching a Fasciclin 2 expression threshold where its non-cell autonomous function stops growth. NCAM-type proteins have been shown to require homophilic cis interactions for trans binding homophilic functional adhesion, and it has been proposed that they are required to build membrane molecular zippers. Thus, Fas2 may be incorporated in the plasma membrane as a growing zipper during imaginal disc cell proliferation. Thus, cellular integration of Fasciclin 2 autonomous and non-cell autonomous signaling from neighbor cells may be a key regulator component to orchestrate the rate of intercalary cell proliferation and the final size and shape of an organ.

Arias, R. A., Tomlinson, A. (2025). Decoding a Cell's Fate: How Notch and receptor tyrosine kinase signals specify the Drosophila R7 photoreceptor. Dev Biol, 519:21-29 PubMed ID: 39653132
Summary:
The process by which the Drosophila R7 photoreceptor is specified has become a classic model for understanding how cell-cell signals direct cell fates. In the R7 precursor cell, both the Notch and receptor tyrosine kinase (RTK) signaling pathways are active, and the information they encode directs the specification of the R7 photoreceptor identity. In this process, Notch performs three distinct functions: it both opposes and promotes the actions of the RTK pathway to specify the photoreceptor fate, and it determines the type of photoreceptor that is specified. The RTK pathway drives transcription of phyl - a gene expression necessary for photoreceptor specification. Notch activity is shown to induce transcription of the yan gene which encodes a transcriptional repressor of phyl. This defines an antagonism between the two pathways, with RTK promoting and Notch opposing phyl transcription. Previous work showed that Notch activity supplies Sevenless to the R7 precursor to allow the RTK pathway hyperactivation required to overcome the Notch repression, and we now identify the regulation of Yan activity as a site of integration of RTK and Notch signaling pathways. Once the cell is specified as a photoreceptor, the third Notch function then prevents seven-up (svp) transcription. The Svp transcription factor directs the R1/6 photoreceptor fate, and the prevention of its expression ensures the default R7 specification.

Zhang, J., Tsutsui, Y., Li, H., Li, T., Wang, Y., Laraki, S., Alarcon-Frias, S., Stayrook, S. E., Klein, D. E. (2025). Structural basis for the interaction between the Drosophila RTK Sevenless (dROS1) and the GPCR BOSS. Nature communications, 16(1):808 PubMed ID: 39827240
Summary:
Sevenless, the Drosophila homologue of ROS1 (herein, dROS1) is a receptor tyrosine kinase (RTK) essential for the differentiation of Drosophila R7 photoreceptor cells. Activation of dROS1 is mediated by binding to the extracellular region (ECR) of the GPCR (G protein coupled receptor) BOSS (Bride Of Sevenless) on adjacent cells. Activation of dROS1 by BOSS leads to subsequent downstream signaling pathways including SOS (Son of Sevenless). However, the physical basis for how dROS1 interacts with BOSS has long remained unknown. This study provides a cryo-EM structure of the dROS1 extracellular region, which mediates ligand binding. The extracellular region of dROS1 adopts a folded-over conformation stabilized by an N-terminal domain comprised of two disulfide stapled helical hairpins. The interacting binding epitopes on both dROS1 and BOSS was further narrowed down using hydrogen-deuterium exchange mass spectrometry (HDX-MS). This includes beta-strands in dROS1's third Fibronectin type III (FNIII) domain and a C-terminal peptide in the BOSS ECR. Mutagenesis studies, coupled with AlphaFold complex predictions, support a binding interaction mediated by a hydrophobic interaction and beta-strand augmentation between these regions. These findings provide a fundamental understanding of the regulatory function of dROS1 and further provide mechanistic insight into the human ortholog and oncogene ROS1.

Nelson, J. O., Slicko, A., Raz, A. A., Yamashita, Y. M. (2025). Insulin signaling regulates R2 retrotransposon expression to orchestrate transgenerational rDNA copy number maintenance. Nature communications, 16(1):399 PubMed ID: 39755735
Summary:
Preserving a large number of essential yet highly unstable ribosomal DNA (rDNA) repeats is critical for the germline to perpetuate the genome through generations. Spontaneous rDNA loss must be countered by rDNA copy number (CN) expansion. Germline rDNA CN expansion is best understood in Drosophila melanogaster, which relies on unequal sister chromatid exchange (USCE) initiated by DNA breaks at rDNA. The rDNA-specific retrotransposon R2 responsible for USCE-inducing DNA breaks is typically expressed only when rDNA CN is low to minimize the danger of DNA breaks; however, the underlying mechanism of R2 regulation remains unclear. This study identifired the insulin receptor (InR) as a major repressor of R2 expression, limiting unnecessary R2 activity. Through single-cell RNA sequencing, male germline stem cells (GSCs), the major cell type that undergoes rDNA CN expansion, were found to have reduced InR expression when rDNA CN is low. Reduced InR activity in turn leads to R2 expression and CN expansion. Dietary manipulation was found to alters R2 expression and rDNA CN expansion activity. This work reveals that the insulin pathway integrates rDNA CN surveying with environmental sensing, revealing a potential mechanism by which diet exerts heritable changes to genomic content.

Nelson, K. A., Lenhart, K. F., Anllo, L., DiNardo, S. (2025). The Drosophila hematopoietic niche assembles through collective cell migration controlled by neighbor tissues and Slit-Robo signaling. eLife, 13 PubMed ID: 39750120
Summary:
Niches are often found in specific positions in tissues relative to the stem cells they support. Consistency of niche position suggests that placement is important for niche function. However, the complexity of most niches has precluded a thorough understanding of how their proper placement is established. To address this, the formation of a genetically tractable niche, the Drosophila Posterior Signaling Center (PSC) was investigated, the assembly of which had not been previously explored. This niche controls hematopoietic progenitors of the lymph gland (LG). PSC cells were previously shown to be specified laterally in the embryo, but ultimately reside dorsally, at the LG posterior. Using live-imaging, this study showed that PSC cells migrate as a tight collective and associate with multiple tissues during their trajectory to the LG posterior. Slit emanating from two extrinsic sources, visceral mesoderm and cardioblasts (heart progenitors), is required for the PSC to remain a collective, and for its attachment to cardioblasts during migration. Without proper Slit-Robo signaling, PSC cells disperse, form aberrant contacts, and ultimately fail to reach their stereotypical position near progenitors. Thisr work characterizes a novel example of niche formation and identifies an extrinsic signaling relay that controls precise niche positioning.

Monday September 14th - Larval and Adult Neural Development, Structure, and Function

Zhang, S., Li, K., Luo, Z., Xu, M., Zheng, S. (2025). A Bio-Inspired Visual Neural Model for Robustly and Steadily Detecting Motion Directions of Translating Objects Against Variable Contrast in the Figure-Ground and Noise Interference. Biomimetics (Basel), 10(1) PubMed ID: 39851767
Summary:
At present, the bio-inspired visual neural models have made significant achievements in detecting the motion direction of the translating object. The responses of the lobula plate tangential cell (LPTC) neurons of Drosophila are robust and stable in the face of variable contrast in the figure-ground and environmental noise interference, which provides an excellent paradigm for addressing these challenges. To resolve these challenges, a bio-inspired visual neural model is proposed, which consists of four stages. 1. The photoreceptors (R1-R6) are utilized to perceive the change in luminance. 2. The change in luminance is divided into parallel ON and OFF pathways based on the lamina monopolar cell (LMC), and the spatial denoising and the spatio-temporal lateral inhibition (LI) can suppress environmental noise and improve motion boundaries. 3. The non-linear instantaneous feedback mechanism in divisive contrast normalization is adopted to reduce local contrast sensitivity; further, the parallel ON and OFF contrast pathways are activated. 4. The parallel motion and contrast pathways converge on the LPTC in the lobula complex. This study draws four conclusions. 1. The effectiveness of the contrast neural computation and the spatial denoising mechanism is verified by the ablation study. 2. This model can robustly detect the motion direction of the translating object against variable contrast in the figure-ground. 3. This model can effectively reduce the fluctuation in this model response against variable contrast in the figure-ground and environmental noise interference. 4. The robustness and stability of this model are further verified by comparing other early visual pre-processing mechanisms and engineering denoising methods. This model can robustly and steadily detect the motion direction of the translating object under variable contrast in the figure-ground and environmental noise interference (Note: This abstract was heavily edited).

Neuman, S. D., Thakur, R. S., Gratz, S. J., O'Connor-Giles, K. M., Bashirullah, A. (2024). Neurodegenerative and neurodevelopmental roles for bulk lipid transporters VPS13A and BLTP2 in movement disorders. bioRxiv, PubMed ID: 39803515
Summary:
Bridge-like lipid transfer proteins (BLTPs) mediate bulk lipid transport at membrane contact sites. Mutations in BLTPs are linked to both early-onset neurodevelopmental and later-onset neurodegenerative diseases, including movement disorders. The tissue specificity and temporal requirements of BLTPs in disease pathogenesis remain poorly understood. This study sought to determine the age-of-onset and tissue-specific roles of VPS13A and BLTP2 in movement disorder pathogenesis using Drosophila models. Tissue-specific knockdowns of the VPS13A ortholog (Vps13) and the BLTP2 ortholog (hobbit) were generated in neurons and muscles of Drosophila. Age-dependent locomotor behavior, neurodegeneration, and synapse development and function were analyzed. Neuron-specific loss of the Vps13 ortholog caused neurodegeneration followed by age- onset movement deficits and reduced lifespan, while muscle-specific loss affected only lifespan, revealing neurodegeneration and myopathy as independent comorbidities in VPS13A disease. In contrast, neuronal loss of the BLTP2 ortholog resulted in severe early-onset locomotor defects without neurodegeneration, while muscle loss impaired synaptogenesis and neurotransmission at the neuromuscular junction (NMJ). It is concluded that VPS13A maintains neuronal survival, while BLTP2 orchestrates synaptic development. VPS13A function in muscle does not play a role in movement defects. The phenotypic specificity of BLTP function provides mechanistic insights into distinct disease trajectories for BLTP-associated movement disorders.

Zheng, T., Long, K., Wang, S., Rui, M. (2025). Glial-derived TNF/Eiger signaling promotes somatosensory neurite sculpting. Cell Mol Life Sci, 82(1):47 PubMed ID: 39833565
Summary:
The selective elimination of inappropriate projections is essential for sculpting neural circuits during development. The class IV dendritic arborization (C4da) sensory neurons of Drosophila remodel the dendritic branches during metamorphosis. Glial cells in the central nervous system (CNS), are required for programmed axonal pruning of mushroom body (MB) γ neurons during metamorphosis in Drosophila. However, it is entirely unknown whether the glial cells are involved in controlling the neurite pruning of C4da sensory neurons. This study shows that glial deletion of Eiger (Egr), orthologous to mammalian tumor necrosis factor TNF superfamily ligand, results in dendrite remodeling deficiency of Drosophila C4da sensory neurons. Moreover, the attenuation of neuronal Wengen (Wgn) and Grindelwald (Grnd), the receptors for TNF ligands, was also examined for defects in dendrite remodeling. It was further discover that Wgn and Grnd facilitate dendrite elimination through JNK Signaling. Overall, these findings demonstrate that glial-derived Egr signal links to the neuronal receptor Wgn/Grnd, activating the JNK signaling pathway and promoting developmental neuronal remodeling. Remarkably, these findings reveal a crucial role of peripheral glia in dendritic pruning of C4da neurons.

Rabah, Y., Berwick, J. P., Sagar, N., Pasquer, L., PlaCais, P. Y., Preat, T. (2025). Astrocyte-to-neuron H(2)O(2) signalling supports long-term memory formation in Drosophila and is impaired in an Alzheimer's disease model. Nature metabolism, 7(2):321-335 PubMed ID: 39856222
Summary:
Astrocytes help protect neurons from potential damage caused by reactive oxygen species (ROS). While ROS can also exert beneficial effects, it remains unknown how neuronal ROS signalling is activated during memory formation , and whether astrocytes play a role in this process. This study discovered an astrocyte-to-neuron H₂O₂ signalling cascade in Drosophila that is essential for long-term memory formation. Stimulation of astrocytes by acetylcholine induces an increase in intracellular calcium ions, which triggers the generation of extracellular superoxide by astrocytic NADPH oxidase. Astrocyte-secreted superoxide dismutase 3 (Sod3) converts superoxide to hydrogen peroxide H₂O₂, which is imported into neurons of the olfactory memory centre, the mushroom body, as revealed by in vivo , and whether astrocytes play a role in this process. This study discovered an astrocyte-to-neuron H₂O₂ imaging. Notably, Sod3 activity requires copper ions, which are supplied by neuronal amyloid precursor protein. This study also found that human amyloid-β peptide, implicated in Alzheimer's disease, inhibits the nAChRα7 astrocytic cholinergic receptor and impairs memory formation by preventing H₂O₂ synthesis. These findings may have important implications for understanding the aetiology of Alzheimer's disease.

Wint, R., Cleary, M. D. (2024). Transfer RNA Levels Are Tuned to Support Differentiation During Drosophila Neurogenesis. Genes, 15(12) PubMed ID: 39766869
Summary:
Neural differentiation requires a multifaceted program to alter gene expression along the proliferation to the differentiation axis. While critical changes occur at the level of transcription, post-transcriptional mechanisms allow fine-tuning of protein output. This study investigated the role of tRNAs in regulating gene expression during neural differentiation in Drosophila larval brains. tRNA abundance in neural progenitor-biased and neuron-biased brains was quantified using the hydrotRNA-seq method. These tRNA data were combined with cell type-specific mRNA decay measurements and transcriptome profiles in order to model how tRNA abundance affects mRNA stability and translation efficiency. It was found that (1) tRNA abundance is largely constant between neural progenitors and neurons but significant variation exists for 10 nuclear tRNA genes and 8 corresponding anticodon groups, (2) tRNA abundance correlates with codon-mediated mRNA decay in neuroblasts and neurons, but does not completely explain the different stabilizing or destabilizing effects of certain codons, and (3) changes in tRNA levels support a shift in translation optimization from a program supporting proliferation to a program supporting differentiation. These findings reveal coordination between tRNA expression and codon usage in transcripts that regulate neural development.

Wang, Q., Miles, L., Wang, S., Noristani, H. N., Monahan Vargas, E. J., Powell, J., O'Rourke-Ibach, S. J., Li, S., Song, Y. (2024). Targeting and anchoring the mechanosensitive ion channel Piezo to facilitate its inhibition of axon regeneration. bioRxiv, PubMed ID: 39763921
Summary:
Mechanical force orchestrates a myriad of cellular events including inhibition of axon regeneration, by locally activating the mechanosensitive ion channel Piezo enriched at the injured axon tip. However, the cellular mechanics underlying Piezo localization and function remains poorly characterized. The RNA repair/splicing enzyme Rtca acts upstream of Piezo to modulate its expression and transport/targeting to the plasma membrane via Rab10 GTPase, whose expression also relies on Rtca. Loss or gain of function of Rab10 promotes or impedes Drosophila sensory neuron axon regeneration, respectively. Rab10 mediates the cell surface expression of integrin β1 (Itgb1)/mys, which colocalizes and genetically interacts with Piezo, facilitating its anchorage and engagement with the microenvironment, and subsequent activation of mechanotransduction to inhibit regeneration. Importantly, loss of Rtca, Rab10 or Itgb1 promotes CNS axon regeneration after spinal cord injury or optic nerve crush in adult mice, indicating the evolutionary conservation of the machinery.

Thursday September 10th - Cell Cycle

Zakerzade, R., Chang, C. H., Chatla, K., Krishnapura, A., Appiah, S. P., Zhang, J., Unckless, R. L., Blumenstiel, J. P., Bachtrog, D., Wei, K. H. (2025). Diversification and recurrent adaptation of the synaptonemal complex in Drosophila PLoS genetics, 21(1):e1011549 PubMed ID: 39804957
Summary:
The synaptonemal complex (SC) is a protein-rich structure essential for meiotic recombination and faithful chromosome segregation. Acting like a zipper to paired homologous chromosomes during early prophase I, the complex is a symmetrical structure where central elements are connected on two sides by the transverse filaments to the chromatin-anchoring lateral elements. Despite being found in most major eukaryotic taxa implying a deeply conserved evolutionary origin, several components of the complex exhibit unusually high rates of sequence turnover. This is puzzlingly exemplified by the SC of Drosophila, where the central elements and transverse filaments display no identifiable homologs outside of the genus. This study exhaustively examined the evolutionary history of the SC in Drosophila taking a comparative phylogenomic approach with high species density to circumvent obscured homology due to rapid sequence evolution. Contrasting starkly against other genes involved in meiotic chromosome pairing, SC genes show significantly elevated rates of coding evolution due to a combination of relaxed constraint and recurrent, widespread positive selection. In particular, the central element cona and transverse filament testes expression. Surprisingly, the expression of SC genes in the germline is prone to change suggesting recurrent regulatory evolution which, in many species, resulted in high testes expression even though Drosophila males are achiasmic. Overall, this study recapitulates the poor conservation of SC components, and further uncovers that the lack of conservation extends to other modalities including copy number, genomic locale, and germline regulation. Considering the elevated testes expression in many Drosophila species and the common ancestor, it is suggested that the activity of SC genes in the male germline, while still poorly understood, may be a prime target of constant evolutionary pressures driving repeated adaptations and innovations.

Shapiro, J. G., Changela, N., Jang, J. K., Joshi, J. N., McKim, K. S. (2025). Distinct checkpoint and homolog biorientation pathways regulate meiosis I in Drosophila oocytes. PLoS genetics, 21(1):e1011400 PubMed ID: 39879252
Summary:
Mitosis and meiosis have two mechanisms for regulating the accuracy of chromosome segregation: error correction and the spindle assembly checkpoint (SAC). This study investigated the function of several checkpoint proteins in meiosis I of Drosophila oocytes. Increased localization of several SAC proteins was found upon depolymerization of microtubules by colchicine. However, unattached kinetochores or errors in biorientation of homologous chromosomes do not induce increased SAC protein localization. Furthermore, the metaphase I arrest does not depend on SAC genes, suggesting the APC is inhibited even if the SAC is not functional. Two SAC proteins, ROD of the ROD-ZW10-Zwilch (RZZ) complex and MPS1, are also required for the biorientation of homologous chromosomes during meiosis I, suggesting an error correction function. Both proteins aid in preventing or correcting erroneous attachments and depend on SPC105R for localization to the kinetochore. This study defined a region of SPC105R, amino acids 123-473, that is required for ROD localization and biorientation of homologous chromosomes at meiosis I. Surprisingly, ROD removal from kinetochores and movement towards spindle poles, termed "streaming," is independent of the dynein adaptor Spindly and is not linked to the stabilization of end-on attachments. Instead, meiotic RZZ streaming appears to depend on cell cycle stage and may be regulated independently of kinetochore attachment or biorientation status. We also show that Spindly is required for biorientation at meiosis I, and surprisingly, the direction of RZZ streaming.

Xu, Y., Chao, A., Rinaldin, M., Kickuth, A., Brugues, J., Di Talia, S. (2025). The cell cycle oscillator and spindle length set the speed of chromosome separation in Drosophila embryos. Current biology : CB, 35(3):655-664.e653 PubMed ID: 39793565
Summary:
Anaphase is tightly controlled spatiotemporally to ensure proper separation of chromosomes.] The mitotic spindle, the self-organized microtubule structure driving chromosome segregation, scales in size with the available cytoplasm. Yet, the relationship between spindle size and chromosome movement remains poorly understood. This study addresses this relationship during the cleavage divisions of the Drosophila blastoderm. The speed of chromosome separation is shown to gradually decrease during the four nuclear divisions of the blastoderm. This reduction in speed is accompanied by a similar reduction in spindle length, ensuring that these two quantities are tightly linked. Using a combination of genetic and quantitative imaging approaches, two processes were found to contribute to controlling the speed at which chromosomes move in anaphase: the activity of molecular motors important for microtubule depolymerization and sliding and the cell cycle oscillator. Specifically, wthe levels of multiple kinesin-like proteins important for microtubule depolymerization, as well as kinesin-5, were found to contribute to setting the speed of chromosome separation. This observation is further supported by the scaling of poleward flux rate with the length of the spindle. Perturbations of the cell cycle oscillator using heterozygous mutants of mitotic kinases and phosphatases revealed that the duration of anaphase increases during the blastoderm cycles and is the major regulator of chromosome velocity. Thus, this work suggests a link between the biochemical rate of mitotic exit and the forces exerted by the spindle. Collectively, it is proposed that the cell cycle oscillator and spindle length set the speed of chromosome separation in anaphase.

Rombouts, J., Tavella, F., Vandervelde, A., Phong, C., Ferrell, J. E., Jr., Yang, Q., Gelens, L. (2025). Mechanistic origins of temperature scaling in the early embryonic cell cycle. Journa;, bioRxiv, PubMed ID: PubMed ID: 39763717
Summary:
Temperature profoundly impacts organismal physiology and ecological dynamics, particularly affecting ectothermic species and making them especially vulnerable to climate changes. Although complex physiological processes usually involve dozens of enzymes, empirically it is found that the rates of these processes often obey the Arrhenius equation, which was originally proposed for individual chemical reactions. This study has examined the temperature scaling of the early embryonic cell cycle, with the goal of understanding why the Arrhenius equation approximately holds and why it breaks down at temperature extremes. Using experimental data from Xenopus laevis, Xenopus tropicalis, and Danio rerio, plus published data from Caenorhabditis elegans, Caenorhabditis briggsae, and Drosophila melanogaster, this study found that the apparent activation energies (E (a) values) for the early embryonic cell cycle for diverse ectotherms are all similar, 75 ∓ 7 kJ/mol, which corresponds to a Q (10) value at 20°C of 2.8 ∓ 0.2. Using computational models, this study found that the approximate Arrhenius scaling and the deviations from it at high and low temperatures can be accounted for by biphasic temperature scaling in critical individual components of the cell cycle oscillator circuit, by imbalances in the E(a) values for different partially rate-determining enzymes, or by a combination of both. Experimental studies of cycling Xenopus extracts indicate that both of these mechanisms contribute to the general scaling of temperature, and in vitro studies of individual cell cycle regulators confirm that there is in fact a substantial imbalance in their E(a) values. These findings provide mechanistic insights into the dynamic interplay between temperature and complex biochemical processes, and into why biological systems fail at extreme temperatures.

Wong, S. S., Monteiro, J. M., Chang, C. C., Peng, M., Mohamad, N., Steinacker, T. L., Xiao, B., Saurya, S., Wainman, A., Raff, J. W. (2025). Centrioles generate two scaffolds with distinct biophysical properties to build mitotic centrosomes. Science advances, 11(6):eadq9549 PubMed ID: 39919171
Summary:
Mitotic centrosomes assemble when centrioles recruit large amounts of pericentriolar material (PCM) around themselves. The PCM comprises hundreds of proteins, and there is much debate about its physical nature. This study shows that Drosophila Spd-2 (human CEP192) fluxes out from centrioles, recruiting Polo and Aurora A kinases to catalyze the assembly of two distinct mitotic-PCM scaffolds: a Polo-dependent Cnn scaffold, and an Aurora A-dependent TACC scaffold, which exhibit solid- and liquid-like behaviors, respectively. Both scaffolds can independently recruit PCM proteins, but both are required for proper centrosome assembly, with the Cnn scaffold providing mechanical strength, and the Transforming acidic coiled-coil protein (TACC) scaffold concentrating centriole and centrosome proteins. Recruiting Spd-2 to synthetic beads injected into early embryos reconstitutes key aspects of mitotic centrosome assembly on the bead surface, and this depends on Spd-2's ability to recruit Polo and Aurora A. Thus, Spd-2 orchestrates the assembly of two scaffolds, with distinct biophysical properties, that cooperate to build mitotic somes in flies.

Kemp, J. P., Jr., Geisler, M. S., Hoover, M., Cho, C. Y., O'Farrell, P. H., Marzluff, W. F., Duronio, R. J. (2024). Cell cycle-regulated transcriptional pausing of Drosophila replication-dependent histone genes. bioRxiv, PubMed ID: 39763942
Summary:
Coordinated expression of replication-dependent (RD) histones genes occurs within the Histone Locus Body (HLB) during S phase, but the molecular steps in transcription that are cell cycle regulated are unknown. This study reports that Drosophila RNA Pol II promotes HLB formation and is enriched in the HLB outside of S phase, including G1-arrested cells that do not transcribe RD histone genes. In contrast, the transcription elongation factor Spt6 is enriched in HLBs only during S phase. Proliferating cells in the wing and eye primordium express full-length histone mRNAs during S phase but express only short nascent transcripts in cells in G1 or G2 consistent with these transcripts being paused and then terminated. Full-length transcripts are produced when Cyclin E/Cdk2 is activated as cells enter S phase. Thus, activation of transcription elongation by Cyclin E/Cdk2 and not recruitment of RNA pol II to the HLB is the critical step that links histone gene expression to cell cycle progression in Drosophila.

Tuesday, September 8th - Transcriptional Regulation

Zakerzade, R., Chang, C. H., Chatla, K., Krishnapura, A., Appiah, S. P., Zhang, J., Unckless, R. L., Blumenstiel, J. P., Bachtrog, D., Wei, K. H. (2025). Diversification and recurrent adaptation of the synaptonemal complex in Drosophila PLoS Genet, 21(1):e1011549 PubMed ID: 39804957
Summary:
The synaptonemal complex (SC) is a protein-rich structure essential for meiotic recombination and faithful chromosome segregation. Acting like a zipper to paired homologous chromosomes during early prophase I, the complex is a symmetrical structure where central elements are connected on two sides by the transverse filaments to the chromatin-anchoring lateral elements. Despite being found in most major eukaryotic taxa implying a deeply conserved evolutionary origin, several components of the complex exhibit unusually high rates of sequence turnover. This is puzzlingly exemplified by the SC of Drosophila, where the central elements and transverse filaments display no identifiable homologs outside of the genus. This study exhaustively examined the evolutionary history of the SC in Drosophila taking a comparative phylogenomic approach with high species density to circumvent obscured homology due to rapid sequence evolution. Contrasting starkly against other genes involved in meiotic chromosome pairing, SC genes show significantly elevated rates of coding evolution due to a combination of relaxed constraint and recurrent, widespread positive selection. In particular, the central element cona and transverse filament testes expression. Surprisingly, the expression of SC genes in the germline is prone to change suggesting recurrent regulatory evolution which, in many species, resulted in high testes expression even though Drosophila males are achiasmic. Overall, this study recapitulates the poor conservation of SC components, and further uncovers that the lack of conservation extends to other modalities including copy number, genomic locale, and germline regulation. Considering the elevated testes expression in many Drosophila species and the common ancestor, it is suggested that the activity of SC genes in the male germline, while still poorly understood, may be a prime target of constant evolutionary pressures driving repeated adaptations and innovations.

Wong, S. S., Monteiro, J. M., Chang, C. C., Peng, M., Mohamad, N., Steinacker, T. L., Xiao, B., Saurya, S., Wainman, A., Raff, J. W. (2025). Centrioles generate two scaffolds with distinct biophysical properties to build mitotic centrosomes. Science advances, 11(6):eadq9549 PubMed ID: 39919171
Summary:
Mitotic centrosomes assemble when centrioles recruit large amounts of pericentriolar material (PCM) around themselves. The PCM comprises hundreds of proteins, and there is much debate about its physical nature. This study shows that Drosophila Spd-2 (human CEP192) fluxes out from centrioles, recruiting Polo and A HREF="../dbzhnsky/auroraa1.htm">Aurora A kinases to catalyze the assembly of two distinct mitotic-PCM scaffolds: a Polo-dependent Cnn scaffold, and an Aurora A-dependent TACC scaffold, which exhibit solid- and liquid-like behaviors, respectively. Both scaffolds can independently recruit PCM proteins, but both are required for proper centrosome assembly, with the Cnn scaffold providing mechanical strength, and the Transforming acidic coiled-coil protein (TACC) scaffold concentrating centriole and centrosome proteins. Recruiting Spd-2 to synthetic beads injected into early embryos reconstitutes key aspects of mitotic centrosome assembly on the bead surface, and this depends on Spd-2's ability to recruit Polo and Aurora A. Thus, Spd-2 orchestrates the assembly of two scaffolds, with distinct biophysical properties, that cooperate to build mitotic somes in flies.

Tuesday, September 8th - Transcriptional Regulation

Fujioka, M., Ke, W., Schedl, P., Jaynes, J. B. (2025). The homie insulator has sub-elements with different insulating and long-range pairing properties. bioRxiv, PubMed ID: 39896478
Summary:
Chromatin insulators are major determinants of chromosome architecture. Specific architectures induced by insulators profoundly influence nuclear processes, including how enhancers and promoters interact over long distances and between homologous chromosomes. Insulators can pair with copies of themselves in trans to facilitate homolog pairing. They can also pair with other insulators, sometimes with great specificity, inducing long-range chromosomal loops. Contrary to their canonical function of enhancer blocking, these loops can bring distant enhancers and promoters together to activate gene expression, while at the same time blocking other interactions in cis. The details of these effects depend on the choice of pairing partner, and on the orientation specificity of pairing, implicating the 3-dimensional architecture as a major functional determinant. This study dissected the homie insulator from the Drosophila even skipped (eve) locus, to understand its substructure. Pairing function were tested based on homie-carrying transgenes interacting with endogenous eve. The assay is sensitive to both pairing strength and orientation. Using this assay, a Su(Hw) binding site in homie was found to be required for efficient long-range interaction, although some activity remains without it. This binding site also contributes to the canonical insulator activities of enhancer blocking and barrier function. Based on this and other results from the functional dissection, each of the canonical insulator activities, chromosomal loop formation, enhancer blocking, and barrier activity, are partially separable. These results show the complexity inherent in insulator functions, which can be provided by an array of different proteins with both shared and distinct properties.

Wood, J. L., Nepal, S., Jones, B. W. (2025). Autoregulation of the glial gene reversed polarity in Drosophila. Scientific reports, 15(1):1238 PubMed ID: 39774987
Summary:
During development, cells of the nervous system begin as unspecified precursors and proceed along one of two developmental paths to become either neurons or glia. Work in the fruit fly Drosophila melanogaster has established the role of the transcription factor Glial cells missing (Gcm) in directing neuronal precursor cells to assume a glial cell fate. Gcm acts on many target genes, one of which is reversed polarity (repo). repo encodes a homeodomain transcription factor and is necessary for the terminal differentiation of glial cells. Transient Gcm expression is followed by maintained expression of repo. Evidence supports autoregulation to be one of the mechanisms that maintains repo expression, as ectopic repo expression in embryos can activate repo-lacZ reporter constructs. This paper further explores the ability of repo to activate reporter constructs in transgenic embryos and in cultured S2 cells. Further evidence is provided that Repo protein acts as a transcription factor on its own regulatory DNA sequence. Three canonical Repo binding sites (RBSs) are located within the upstream 4.3 kilobase repo cis-regulatory DNA (CRD). The upstream 2 kb within the repo CRD has remarkable repo-dependent gene expression activity, and mutagenesis of RBS1 in this 2 kb region results in a significant decrease in repo-induced reporter gene expression in both systems. These results in cell culture experiments also show that RBS2 and/or RBS3 can affect repo-dependent gene expression in the context of the whole upstream repo CRD. Mutagenesis of both RBS2 and RBS3 in the repo CRD, leaving RBS1 intact, significantly reduces repo-induced reporter gene expression. These results suggest that all three canonical RBSs may be cooperatively involved in autoregulation of repo expression.

Kudryashova, K. S., Deriglazova, I. O., Osadchiy, I. S., Georgiev, P., Maksimenko, O. (2024). Construction of Promoter Elements for Strong, Moderate, and Weak Gene Expression in Drosophila melanogaster. Genes, 16(1) PubMed ID: 39858550
Summary:
Transcriptional promoters play an essential role in regulating protein expression. Promoters with weak activity generally lead to low levels of expression, resulting in fewer proteins being produced. At the same time, strong promoters are commonly used in studies using transgenic organisms as model systems. This approach can have various negative consequences for the organism, as many regulatory proteins need to be expressed in small quantities, and excessive expression can have harmful effects on cells and organisms. Therefore, it is important to select the right promoter when creating transgenic organisms for research and practical applications. In this study, the Drosophila melanogaster genome was used as a source of natural promoter sequences for RNA polymerase II. These sequences were extracted and used to create a set of promoters that are suitable for practical application. The promoters were tested in a model system using fluorescent reporter genes in S2 cells and transgenic lines of Drosophila. This study assessed the expression levels of fluorescent reporter genes to rank the tested promoters from strongest to weakest. Six individual promoters of different sizes were established and compared. Additionally, three pairs of bidirectional promoters were designed and tested that could be used to simultaneously express two proteins. Based on these findings, the tested promoters were grouped into three categories: strong, moderate, and weak. These promoters can be utilized in transgenic model systems for protein production at different levels, from high to low. Bidirectional promoters, constructed "head-to-head", meaning oppositely directed with the minimum distance between them, represent a novel tool for the co-expression of proteins.

Pimmett, V. L., McGehee, J., Trullo, A., Douaihy, M., Radulescu, O., Stathopoulos, A., Lagha, M. (2025). Optogenetic manipulation of nuclear Dorsal reveals temporal requirements and consequences for transcription. Development, 152(6) PubMed ID: 40018801
Summary:
Morphogen gradients convey essential spatial information during tissue patterning. Although the concentration and timing of morphogen exposure are both crucial, how cells interpret these graded inputs remains challenging to address. This study employed an optogenetic system to acutely and reversibly modulate the nuclear concentration of the morphogen Dorsal (DL), homolog of NF-kappaB, which orchestrates dorsoventral patterning in the Drosophila embryo. By controlling DL nuclear concentration while simultaneously recording target gene outputs in real time, this study identified a critical window for DL action that is required to instruct patterning and characterized the resulting effect on spatiotemporal transcription of target genes in terms of timing, coordination and bursting. A transient decrease was found in nuclear DL levels at nuclear cycle 13 leads to reduced expression of the mesoderm-associated gene snail (sna) and partial derepression of the neurogenic ectoderm-associated target short gastrulation (sog) in ventral regions. Surprisingly, the mispatterning elicited by this transient change in DL was detectable at the level of single-cell transcriptional bursting kinetics, specifically affecting long inter-burst durations. This approach of using temporally resolved and reversible modulation of a morphogen in vivo, combined with mathematical modeling, establishes a framework for understanding the stimulus-response relationships that govern embryonic patterning.

Mukherjee, A., Kapoor, M., Shankta, K., Fallacaro, S., Carter, R. D., Ratchasanmuang, P., Haloush, Y. I., Mir, M. (2025). A cluster of RNA Polymerase II molecules is stably associated with an active gene. bioRxiv, PubMed ID: 39990393
Summary:
In eukaryotic nuclei, transcription is associated with discrete foci of RNA Polymerase II (RNAPII) molecules. How these clusters interact with genes and their impact on transcriptional activity remain heavily debated. This study took advantage of the naturally occurring increase in transcriptional activity during Zygotic Genome Activation (ZGA) in Drosophila melanogaster embryos to characterize the functional roles of RNAPII clusters in a developmental context. Using single-molecule tracking and lattice light-sheet microscopy, this study found that RNAPII cluster formation depends on transcription initiation and that cluster lifetimes are reduced upon transcription elongation. Single clusters are stably associated with active gene loci during transcription and that cluster intensities are strongly correlated with transcriptional output. These data suggest that prior to ZGA, RNAPII clusters prime genes for activation, whereas after ZGA, clusters are composed mostly of elongating molecules at individual genes.

Soldatova, I. V., Shepelev, M. V., Georgiev, P., Tikhonov, M. (2024). A Novel Mechanism for Transcription Termination in the mod(mdg4) Locus of Drosophila melanogaster. Biology, 13(12) PubMed ID: 39765661
Summary:
This study investigated an alternative mechanism of transcription termination that occurs independently of polyadenylation. We focused on a non-canonical transcription terminator (NTT) identified in the mod(mdg4) gene of Drosophila melanogaster. Using a developed model system, we demonstrated that the minimal functional unit of the NTT consists of 79 nucleotides that form a specific secondary RNA structure. Our results indicate that transcripts generated from the NTT exhibit reduced stability and are hindered in their export to the cytoplasm. An NTT from the distantly related species D. willistoni could function as a transcription terminator in D. melanogaster cells, highlighting the importance of conserved motifs for NTT functionality. At the same time, the NTT did not function in human cells, suggesting that the interaction of the NTT with specific protein factors is required to terminate transcription.

Friday, September 4th - Embryonic Development

O'Leary, T. S., Mikucki, E. E., Tangwancharoen, S., Boyd, J. R., Frietze, S., Helms Cahan, S., Lockwood, B. L. (2025). Single-nuclei multiome ATAC and RNA sequencing reveals the molecular basis of thermal plasticity in Drosophila melanogaster embryos. bioRxiv, PubMed ID: 39829925
Summary:
Embryogenesis is remarkably robust to temperature variability, yet there is limited understanding of the homeostatic mechanisms that offset thermal effects during early development. This study measured the thermal acclimation response of upper thermal limits and profiled chromatin state and the transcriptome of D. melanogaster embryos (Bownes Stage 11) using single-nuclei multiome ATAC and RNA sequencing. Thermal acclimation, while preserving a common set of primordial cell types, rapidly shifted the upper thermal limit. Cool-acclimated embryos showed a homeostatic response characterized by increased chromatin accessibility at transcription factor binding motifs for the transcriptional activator Zelda, along with enhanced activity of gene regulatory networks in the primordial cell types including the foregut and hindgut, mesoderm, and peripheral nervous system. In addition, cool-acclimated embryos had higher expression of genes encoding ribosomal proteins and enzymes involved in oxidative phosphorylation. Despite the hypothesis that differential heat tolerance might be explained by differential expression of molecular chaperones, widespread differences in the chromatin accessibility or expression of heat shock genes were not observed. Overall, these results suggest that environmental robustness to temperature during embryogenesis necessitates homeostatic gene expression responses that regulate the speed of development, potentially imposing metabolic costs that constrain upper thermal limits.

Reyes, R., Rodriguez-MuNoz, R., Nahmad, M. (2025). Cell recruitment and the origins of Anterior-Posterior asymmetries in the Drosophila wing. PloS one, 20(1):e0313067 PubMed ID: 39752433
Summary:
The mechanisms underlying the establishment of asymmetric structures during development remain elusive. The wing of Drosophila is asymmetric along the Anterior-Posterior (AP) axis, but the developmental origins of this asymmetry is unknown. This study investigated the contribution of cell recruitment, a process that drives cell fate differentiation in the Drosophila wing disc, to the asymmetric shape and pattern of the adult wing. Genetic impairment of cell recruitment in the wing disc results in a significant gain of AP symmetry, which results from a reduction of the region between longitudinal vein 5 and the wing margin (L5-M) in the adult wing. Morphometric analysis confirms that blocking of cell recruitment results in a more symmetric wing with respect to controls, suggesting a contribution of cell recruitment to the establishment of asymmetry in the adult wing. In order to verify if this phenotype is originated during the time in which cell recruitment occurs during larval development, this study examined the expression of a reporter for the selector gene vestigial (vg) in the corresponding pro-vein regions of the wing disc, but these findings could not explain the findings in adult wings. However, the circularity of the Vg pattern significantly increases in recruitment-impaired wing discs, suggesting that cell recruitment may contribute to AP asymmetries in the adult wing shape by altering the roundness of the Vg pattern. It is concluded that cell recruitment, a widespread mechanism that participates in growth and patterning of several developing systems, may contribute, at least partially, to the asymmetric shape of the Drosophila wing.

Richa, P., Haring, M., Wang, Q., Choudhury, A. R., Gopfert, M. C., Wolf, F., Grosshans, J., Kong, D. (2025). Synchronization in epithelial tissue morphogenesis. Curr Biol, 35(11):2495-2508.e2494 PubMed ID: 40239658
Summary:
Coordination of cell behavior is central to morphogenesis, when arrays of cells simultaneously undergo shape changes or dynamic rearrangements. In epithelia, cell shape changes invariably exert mechanical forces, which adjacent cells could sense to trigger an active response. However, molecular mechanisms for such mechano-transduction and especially their role for tissue-wide coordination in morphogenesis have remained ambiguous. This study investigated the function of Tmc, a key component of cellular mechano-transduction in vertebrate hearing, for coordination of cell dynamics in the epithelial amnioserosa of Drosophila embryos. Cell-cell mechano-transduction was directly probed in vivo by opto-chemically inducing single-cell contractions and discovered a Tmc-dependent contraction response in neighboring cell groups. On the tissue scale; synchronization was discovered of neighboring cell area oscillations, which is impaired in Tmc mutants. A data-driven model of Tmc-dependent cell-cell interactions predicts that synchronization leads to an isotropic force map and effectively shields the tissue from external mechanical pulling. By microdissection, equal junction tension was observed along the axial and lateral axis in wild-type but increased lateral tension in Tmc mutants. Thus, Tmc transduces forces into an intracellular response that coordinates mechanical cell behavior in epithelial tissue.

Linvill, K., Russell, L. J., Vanderleest, T. E., Miao, H., Xie, Y., Blankenship, J. T., Loerke, D. (2025). Rectification of planar orientation angle switches behavior and replenishes contractile junctions. The Journal of cell biology, 224(4) PubMed ID: 39846952
Summary:
In the early Drosophila embryo, germband elongation is driven by oriented cell intercalation through t1 transitions, where vertical (dorsal-ventral aligned) interfaces contract and then resolve into new horizontal (anterior-posterior aligned) interfaces. Contractile events produce a continuous "rectification" of cell interfaces, in which interfaces systematically rotate toward more vertical orientations. As interfaces rotate, their behavior transitions from elongating to contractile regimes, indicating that the planar polarized identities of cell-cell interfaces are continuously re-interpreted in time depending on their orientation angle. Rotating interfaces acquire higher levels of Myosin II motor proteins as they become more vertical, while disruptions to the contractile molecular machinery reduce the rates of rotation. Through this angle rectification, the available pool of contractile interfaces is continuously replenished, as new interfaces acquire a contractile identity through rotation. Thus, individual cells acquire additional interfaces that are capable of undergoing t1 transitions, allowing cells to participate in multiple staggered rounds of intercalation events.

Tah, I., Haertter, D., Crawford, J. M., Kiehart, D. P., Schmidt, C. F., Liu, A. J. (2025). A minimal vertex model explains how the amnioserosa avoids fluidization during Drosophila dorsal closure. Journal Proceedings of the National Academy of Sciences 122(1):e2322732121 PubMed ID: 39793057
Summary:
Dorsal closure is a process that occurs during embryogenesis of Drosophila melanogaster. During dorsal closure, the amnioserosa (AS), a one-cell thick epithelial tissue that fills the dorsal opening, shrinks as the lateral epidermis sheets converge and eventually merge. During this process, both shape index and aspect ratio of amnioserosa cells increase markedly. The standard 2-dimensional vertex model, which successfully describes tissue sheet mechanics in multiple contexts, would in this case predict that the tissue should fluidize via cell neighbor changes. Surprisingly, however, the amnioserosa remains an elastic solid with no such events. This study presents a minimal extension to the vertex model that explains how the amnioserosa can achieve this unexpected behavior. Continuous shrinkage of the preferred cell perimeter and cell perimeter polydispersity lead to the retention of the solid state of the amnioserosa. This model accurately captures measured cell shape and orientation changes and predicts nonmonotonic junction tension that we confirm with laser ablation experiments.

Sokolowski, T. R., Gregor, T., Bialek, W., Tkacik, G. (2025). Deriving a genetic regulatory network from an optimization principle. Proceedings of the National Academy of Sciences 122(1):e2402925121 PubMed ID: 39752518
Summary:
>Many biological systems operate near the physical limits to their performance, suggesting that aspects of their behavior and underlying mechanisms could be derived from optimization principles. However, such principles have often been applied only in simplified models. This study explores a detailed mechanistic model of the gap gene network in the Drosophila embryo, optimizing its 50+ parameters to maximize the information that gene expression levels provide about nuclear positions. This optimization is conducted under realistic constraints, such as limits on the number of available molecules. Remarkably, the optimal networks derived closely match the architecture and spatial gene expression profiles observed in the real organism. This framework quantifies the tradeoffs involved in maximizing functional performance and allows for the exploration of alternative network configurations, addressing the question of which features are necessary and which are contingent. Our results suggest that multiple solutions to the optimization problem might exist across closely related organisms, offering insights into the evolution of gene regulatory networks.

Thursday, September 3rd - Disease Models

Langhammer, F., Gregor, A., Ntamati, N. R., Ekici, A. B., Winner, B., Nevian, T., Zweier, C. (2025). Deregulated ion channels contribute to RHOBTB2-associated developmental and epileptic encephalopathy. Human molecular genetics, 34(7):639-650 PubMed ID: 39849855
Summary:
While de novo missense variants in the BTB domains of atypical RhoGTPase RHOBTB2 cause a severe developmental and epileptic encephalopathy, de novo missense variants in the GTPase domain or bi-allelic truncating variants are associated with more variable neurodevelopmental and seizure phenotypes. Apart from the observation of RHOBTB2 abundance resulting from BTB-domain variants and increased seizure susceptibility in Drosophila overexpressing RhoBTB, knowledge on RHOBTB2-related pathomechanisms is limited. This study now found enrichment for ion channels among the differentially expressed genes from RNA-Seq on fly heads overexpressing RhoBTB. Subsequent genetic interaction experiments confirmed a functional link between RhoBTB and paralytic, the orthologue of human sodium channels, including epilepsy associated SCN1A, in vivo. Patch-clamp recordings were performed on mature neurons differentiated from human induced pluripotent stem cells with either homozygous frameshifts or patient-specific heterozygous missense variants in the GTPase or the BTB domains. This revealed significantly altered neuronal activity and excitability resulting from BTB domain variants but not from GTPase domain variants or upon complete loss of RHOBTB2. This study indicates a role of deregulated ion channels in the pathogenesis of RHOBTB2-related developmental and epileptic encephalopathy and points to specific pathomechanisms underlying the observed genotype-phenotype correlations regarding variant zygosity, location and nature.

Lai, Y., Reina-Gonzalez, P., Maor, G., Miller, G. W., Sarkar, S. (2025). Biotin mitigates the development of manganese-induced, Parkinson's disease-related neurotoxicity in Drosophila and human neurons. Science signaling, 18(870):eadn9868 PubMed ID: 39836750
Summary:
Chronic exposure to manganese (Mn) induces manganism and has been widely implicated as a contributing environmental factor to Parkinson's disease (PD), featuring notable overlaps between the two in motor symptoms and clinical hallmarks. This study developed an adult Drosophila model of Mn toxicity that recapitulated key parkinsonian features, spanning behavioral deficits, neuronal loss, and dysfunctions in lysosomes and mitochondria. Metabolomics analysis of the brain and body tissues of these flies at an early stage of toxicity identified systemic changes in the metabolism of biotin (also known as vitamin B(7)) in Mn-treated groups. Biotinidase-deficient flies showed exacerbated Mn-induced neurotoxicity, parkinsonism, and mitochondrial dysfunction. Supplementing the diet of wild-type flies with biotin ameliorated the pathological phenotypes of concurrent exposure to Mn. Biotin supplementation also ameliorated the pathological phenotypes of three standard fly models of PD. Furthermore, supplementing the culture media of human induced stem cells (iPSCs) differentiated midbrain dopaminergic neurons with biotin protected against Mn-induced mitochondrial dysregulation, cytotoxicity, and neuronal loss. Last, analysis of the expression of genes encoding biotin-related proteins in patients with PD revealed increased amounts of biotin transporters in the substantia nigra compared with healthy controls, suggesting a potential role of altered biotin metabolism in PD. Together, these findings identified changes in biotin metabolism as underlying Mn neurotoxicity and parkinsonian pathology in flies, for which dietary biotin supplementation was preventative.

Sun, Z., Li, L., Zhang, L. (2025). Apigenin enhancing oxidative resistance and proteostasis to extend lifespan via PTEN-mediated AKT signalling pathway. Biochim Biophys Acta Mol Basis Dis, 1871(3):167670 PubMed ID: 39826849
Summary:
Aging is a complicated process, featuring the progressive deterioration of physiological functions and a heightened susceptibility to diseases including neurodegenerative disorders, cardiovascular diseases, and cancer. Apigeninoxidative stress in both organisms, as manifested by enhanced survival, decreased reactive oxygen species (ROS) levels and upregulation of antioxidant enzymes. Furthermore, apigenin activates crucial elements of the proteostasis network (PN), such as upregulation of proteostasis-related enzymes activity and genes expression. Network analysis revealed that apigenin affects aging conserved in the longevity-regulating pathway. Notably, Pten is a hub target in flies. Apigenin regulated DmPten at both mRNA and protein expression level while modulating downstream targets, including the phosphorylation of AKT and associated signalling pathways. In a high-sucrose diet (HSD) model, Apigenin treatment extended lifespan, reduced hemolymph glucose levels, enhanced Pten expression, suppressed AKT phosphorylation, and modulated the phosphorylation status of S6K and expression of DmFoxo. These results demonstrate that apigenin could serve as a longevity research object and potential therapeutic drug for promoting health and longevity through its antioxidant and proteostatic properties.

Singh, A., Hu, Y., Lopes, R. F., Lane, L., Woldemichael, H., Xu, C., Udeshi, N. D., Carr, S. A., Perrimon, N. (2025). Cell-death induced immune response and coagulopathy promote cachexia in Drosophila. bioRxiv, PubMed ID: 39829769
Summary:
Tumors can exert a far-reaching influence on the body, triggering systemic responses that contribute to debilitating conditions like cancer cachexia. To characterize the mechanisms underlying tumor-host interactions, this study utilized a BioID-based proximity labeling method to identify proteins secreted by Yki^act adult Drosophila gut tumors into the bloodstream/hemolymph. Among the major proteins identified are coagulation and immune-responsive factors that contribute to the systemic wasting phenotypes associated with Yki^act tumors. The effect of innate immunity factors is mediated by NFkappaB transcription factors Relish, Dorsal, and Dif, which in turn upregulate the expression of the cachectic factors Pvf1, Impl2, and Upd3. In addition, Yki^act tumors secrete Eiger, a TNF-alpha homolog, which activates the JNK signaling pathway in neighboring non-tumor cells, leading to cell death. The release of damage-associated molecular patterns (DAMPs) from these dying cells presumably amplifies the inflammatory response, exacerbating systemic wasting. Targeting the inflammatory response, the JNK pathway, or the production of cachectic factors could potentially alleviate the debilitating effects of cancer cachexia.

Oh, J., Catherine, C., Kim, E. S., Min, K. W., Jeong, H. C., Kim, H., Kim, M., Ahn, S. H., Lukianenko, N., Jo, M. G., Bak, H. S., Lim, S., Kim, Y. K., Kim, H. M., Lee, S. B., Cho, H. (2025). Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin. Nature communications, 16(1):737 PubMed ID: 39824813
Summary:
Toxic protein aggregates are associated with various neurodegenerative diseases, including Huntington's disease (HD). Since no current treatment delays the progression of HD, this study developed a mechanistic approach to prevent mutant huntingtin (mHttex1) aggregation. This study engineer the ATP-independent cytosolic chaperone PEX19, which targets peroxisomal membrane proteins to peroxisomes, to remove mHttex1 aggregates. Using yeast toxicity-based screening with a random mutant library, two yeast PEX19 variants were identified, and equivalent mutations were engineered into human PEX19 (hsPEX19). These variants effectively delay mHttex1 aggregation in vitro and in cellular HD models. The mutated hydrophobic residue in the α4 helix of hsPEX19 variants binds to the N17 domain of mHttex1, thereby inhibiting the initial aggregation process. Overexpression of the hsPEX19-FV variant rescues HD-associated phenotypes in primary striatal neurons and in Drosophila. Overall, these data reveal that engineering ATP-independent membrane protein chaperones is a promising therapeutic approach for rational targeting of mHttex1 aggregation in HD.

Yu, Z., Yan, J., Liu, Z., Wang, H., Luo, G., Chen, H. (2025). The Batten disease gene Cln3 is required for the activation of intestinal stem cell during regeneration via JAK/STAT signaling in Drosophila. Frontiers in cell and developmental biology, 13:1508714 PubMed ID: 39917569
Summary:
CLN3 mutation causes Juvenile neuronal ceroid lipofuscinosis (JNCL, also known as Batten disease), an early onset neurodegenerative disorder. Patients who suffer from Batten disease often die at an early age. However, the mechanisms underlying how CLN3 loss develops Batten disease remain largely unclear. Using Drosophila midgut system, this study demonstrated that Drosophila Cln3 has no effect on midgut homeostasis maintaince, including cellular component, intestinal stem cells (ISCs) proliferation and differentiation, but is necessary for ISC activation upon tissue damage. Cell type-specific Gal4 screening reveals that the failure of ISC activation during regeneration caused by Cln3 loss is ISC-autonomous. Through genetic analyses, JAK/STAT signaling in ISCs is not activated with Cln3 depletion upon tissue damage, and functions downstream of Cln3. These study provides a potential mechanism underlying the development of CLN3-mediated Batten disease at cellular level.

Wednesday, September 2nd - RNAs

Santos-Cruz, L. F., Campos-Aguilar, M., Castaneda-Partida, L., Sigrist-Flores, S. C., Heres-Pulido, M. E., Duenas-Garcia, I. E., Piedra-Ibarra, E., Jimenez-Flores, R., Ponciano-Gomez, A. (2025). Impact of Larval Sertraline Exposure on Alternative Splicing in Neural Tissue of Adult Drosophila melanogaster. International journal of molecular sciences, 26(2) PubMed ID: 39859278
Summary:
Sertraline, a selective serotonin reuptake inhibitor (SSRI), is commonly used to treat various psychiatric disorders such as depression and anxiety due to its ability to increase serotonin availability in the brain. Recent findings suggest that sertraline may also influence the expression of genes related to synaptic plasticity and neuronal signaling pathways. Alternative splicing, a process that allows a single gene to produce multiple protein isoforms, plays a crucial role in the regulation of neuronal functions and plasticity. Dysregulation of alternative splicing events has been linked to various neurodevelopmental and neurodegenerative diseases. This study aims to explore the effects of sertraline on alternative splicing events, including exon inclusion, exon exclusion, and mutually exclusive splicing events, in genes associated with neuronal function in Drosophila melanogaster and to use this model to investigate the molecular impacts of SSRIs on gene regulation in the nervous system. RNA sequencing (RNA-seq) was performed on central nervous system samples from Drosophila melanogaster adults exposed to sertraline for 24 h when they were third instar larvae. Alternative splicing events were analyzed to identify changes in exon inclusion and exclusion, as well as intron retention. Sertraline treatment significantly altered alternative splicing patterns in key genes related to neuronal stability and function. Specifically, sertraline promoted the inclusion of long Ank2 isoforms, suggesting enhanced axonal stability, and favored long ATPalpha isoforms, which support Na(+)/K(+) ATPase activity essential for ionic balance and neuronal excitability. Intron retention in the yuri gene suggests that cytoskeletal reorganization could impact neuronal morphology. Additionally, splicing alterations in sxc and Atg18a indicate a potential influence of sertraline on epigenetic regulation and autophagy processes, fundamental aspects for neuronal plasticity and cellular homeostasis. These findings suggest that sertraline influences alternative splicing in the central nervous system of Drosophila melanogaster, potentially contributing to its therapeutic effects by modulating neuronal stability and adaptability.

Parikh, R. Y., Nayak, D., Lin, H., Gangaraju, V. K. (2025). Drosophila Modulo is essential for transposon silencing and developmental robustness. The Journal of biological chemistry, 301(3):108210 PubMed ID: 39848495
Summary:
Transposable element (TE) silencing in the germline is crucial for preserving genome integrity; its absence results in sterility and diminished developmental robustness. The Piwi-interacting RNA (piRNA) pathway is the primary small non-coding RNA mechanism by which TEs are silenced in the germline. Three piRNA binding proteins promote the piRNA pathway function in the germline- P-element-induced wimpy testis (Piwi), Aubergine (Aub), and Argonaute 3 (Ago3). Piwi mediates transcriptional silencing of TEs by promoting the deposition of the heterochromatin mark Histone 3 lysine nine trimethylation (H3K9me3) at TE genomic sites. Aub and Ago3 facilitate post-transcriptional silencing of TEs. Proteins and mechanisms that promote piRNA function in TE silencing are still being discovered. This study demonstrates that the Drosophila Modulo protein, a homolog of mammalian Nucleolin and an epigenetic regulator, is crucial for the enrichment of H3K9me3 at TEs. We show that Modulo interacts with Piwi and operates downstream of the Piwi-piRNA complex's entry into the nucleus. Lack of Modulo function impairs Piwi-interacting protein Panoramix's ability to target transposon RNAs. Furthermore, the reduced function of Modulo in the mother undermines developmental robustness and exacerbates neomorphic a specific dominant, gain-of-function mutant allele of the Kruppel, Kr[If-1], induced ectopic eye outgrowths in the offspring. Maternal Modulo enhances developmental robustness by inhibiting TE activation and transcriptome variability associated with intrinsic genetic variation. Thus, Modulo is an essential component of the mechanism that operates in the maternal germline to facilitate TE silencing and ensure developmental robustness in the ensuing generation.

Scarpa, A., Pianezza, R., Gellert, H. R., Haider, A., Kim, B. Y., Lai, E. C., Kofler, R., Signor, S. (2025). Double trouble: two retrotransposons triggered a cascade of invasions in Drosophila species within the last 50 years. Nature communications, 16(1):516 PubMed ID: 39788974
Summary:
Horizontal transfer of genetic material in eukaryotes has rarely been documented over short evolutionary timescales. This study shows that two retrotransposons, Shellder and Spoink, invaded the genomes of multiple species of the melanogaster subgroup within the last 50 years. Through horizontal transfer, Spoink spread in D. melanogaster during the 1980s, while both Shellder and Spoink invaded D. simulans in the 1990s. Possibly following hybridization, D. simulans infected the island endemic species D. mauritiana (Mauritius) and D. sechellia (Seychelles) with both TEs after 1995. In the same approximate time-frame, Shellder also invaded D. teissieri, a species confined to sub-Saharan Africa. The donors of Shellder and Spoink are likely American Drosophila species from the willistoni, cardini, and repleta groups. Thus, the described cascade of TE invasions could only become feasible after D. melanogaster and D. simulans extended their distributions into the Americas 200 years ago, likely aided by human activity. This work reveals that cascades of TE invasions, likely initiated by human-mediated range expansions, could have an impact on the genomic and phenotypic evolution of geographically dispersed species. Within a few decades, TEs could invade many species, including island endemics, with distributions very distant from the donor of the TE.

Liu, M., Xie, X. J., Li, X., Ren, X., Sun, J. L., Lin, Z., Hemba-Waduge, R. U., Ji, J. Y. (2025). Transcriptional coupling of telomeric retrotransposons with the cell cycle.. Science advances, 11(1):eadr2299 PubMed ID: 39752503
Summary:
Unlike most species that use telomerase for telomere maintenance, many dipterans, including Drosophila, rely on three telomere-specific retrotransposons (TRs)-HeT-A, TART, and TAHRE-to form tandem repeats at chromosome ends. Although TR transcription is crucial in their life cycle, its regulation remains poorly understood. This study identifies the Mediator complex, E2F1-Dp, and Scalloped/dTEAD as key regulators of TR transcription. Reducing the activity of the Mediator or Sd/dTEAD increases TR expression and telomere length, while overexpressing E2F1-Dp or depleting Rbf1 stimulates TR transcription. The Mediator and Sd/dTEAD regulate this process through E2F1-Dp. CUT&RUN (Cleavage under targets and release using nuclease) analysis shows direct binding of CDK8, Dp, and Sd/dTEAD to telomeric repeats, with motif enrichment revealing E2F- and TEAD-binding sites. These findings uncover the Mediator complex's role in controlling TR transcription and telomere length through E2F1-Dp and Sd, coupling the transcriptional regulation of the TR life cycle with host cell-cycle machinery to protect chromosome ends in Drosophila.

Li, M., Yu, X., Yao, Z., Gao, X., Liu, Q., Zhou, Z., Zhao, Y. (2025). Targeting the Hh and Hippo pathways by miR-7 suppresses the development of insect wings. Insect science, PubMed ID: 39823176
Summary:
Wings are important organs of insects involved in flight, mating, and other behaviors, and are therefore prime targets for pest control. The formation of insect wings is a complex process that is regulated by multiple pathways. The Hedgehog (Hh) pathway regulates the distribution of wing veins, while the Hippo pathway modulates wing size. Any interventions that can manipulate these pathways have the potential to disrupt wing development and could be used for pest control. This study found that overexpression of miR-7 in Drosophila results in smaller wings with disordered veins. Mechanistically, miR-7 directly targets both ci and yki via different mature miRNAs (miR-7-5p and miR-7-3p), thereby disrupting the Hh and Hippo pathways. Importantly, this regulatory mechanism is also observed in another insect species, Helicoverpa armigera. Finally, by utilizing a nanocarrier delivery system, this study showed that introducing miR-7 via star polycation (SPc), a star-shaped, positively charged nanomaterial used as a carrier for delivering genetic material, leads to wing defects in H. armigera. In conclusion, these findings uncover that miR-7 inhibits wing formation by targeting both the Hippo and Hh pathways, indicating its potential for use in pest control strategies.

Li, J., Xu, S., Liu, Z., Yang, L., Ming, Z., Zhang, R., Zhao, W., Peng, H., Quinn, J. J., Wu, M., Geng, Y., Zhang, Y., He, J., Chen, M., Li, N., Shao, N. Y., Ma, Q. (2025). A noncanonical role of roX RNAs in autosomal epigenetic repression. Nature communications, 16(1):155 PubMed ID: 39747148
Summary:
Long noncoding RNAs known as roX (RNA on the X) are crucial for male development in Drosophila, as their loss leads to male lethality from the late larval stages. While roX RNAs are recognized for their role in sex-chromosome dosage compensation, ensuring balanced expression of X-linked genes in both sexes, their potential influence on autosomal gene regulation remains unexplored. Using an integrative multi-omics approach, this study showed that roX RNAs not only govern the X chromosome but also target genes on autosomes that lack male-specific lethal (MSL) complex occupancy, together with Polycomb repressive complexes (PRCs). This study observed that roX RNAs colocalize with MSL proteins on the X chromosome and PRC components on autosomes. Intriguingly, loss of roX function reduces X-chromosomal H4K16ac levels and autosomal H3K27me3 levels. Correspondingly, X-linked genes display reduced expression, whereas many autosomal genes exhibit elevated expression upon roX loss. These findings propose a dual role for roX RNAs: activators of X-linked genes and repressors of autosomal genes, achieved through interactions with MSL and PRC complexes, respectively. This study uncovers the unconventional epigenetic repressive function of roX RNAs with PRC interaction.

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