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March 2026
February 2026 January 2026 December 2025 November 2025 October 2025 September 2025 August2025 July 2025 June2025 June2025 May 2025 April 2025 March 2025 February 2025 January 2025 December 2024 November 2024 October 2024 September 2024 August 2024 July 2024 June 2024 May 2024 April 2024 March 2024 February 2024 January 2024 December 2022 December 2021 December 2020 December 2019 | Tatar, M., Zheng, W., Yadav, S., Yamamoto, R., Curtis-Joseph, N., Li, S., Wang, L., Parkhitko, A. A. (2025). Mutation of an insulin-sensitive Drosophila insulin-like receptor mutant requires methionine metabolism reprogramming to extend lifespan. bioRxiv, PubMed ID: 40093182
Summary: Insulin/insulin growth factor signaling is a conserved pathway that regulates lifespan across many species. Multiple mechanisms are proposed for how this altered signaling slows aging. To elaborate these causes, a series of Drosophila Insulin-like receptor (dInr) mutants was developed with single amino acid substitutions that extend lifespan but differentially affect insulin sensitivity, growth and reproduction. Transheterozygotes of canonical dInr mutants (Type I) extend longevity and are insulin-resistant, small and weakly fecund. In contrast, a dominant mutation (dInr (353), Type II) within the Kinase Insert Domain (KID) robustly extends longevity but is insulin-sensitive, full-sized, and highly fecund. Transcriptome and metabolome analyses was applied to explore how dInr (353) slows aging without insulin resistance. Type I and II mutants overlap in many pathways but also produce distinct transcriptomic profiles that include differences in innate immune and reproductive functions. In metabolomic analyses, the KID mutant dInr (353) reprograms methionine metabolism in a way that phenocopies dietary methionine restriction, in contrast to canonical mutants which are characterized by upregulation of the transsulfuration pathway. Because abrogation of S-adenosylhomocysteine hydrolase blocks the longevity benefit conferred by dInr (353), it is concluded the methionine cycle reprogramming of Type II is sufficient to slow aging. Metabolomic analysis further revealed the Type II mutant is metabolically flexible: unlike aged wildtype, aged dInr (353) adults can reroute methionine toward the transsulfuration pathway, while Type I mutant flies upregulate the trassulfuration pathway continuously from young age. Altered insulin/insulin growth factor signaling has the potential to slow aging without the complications of insulin resistance by modulating methionine cycle dynamics. | Stefanatos, R., Robertson, F., Castejon-Vega, B., Yu, Y., Uribe, A. H., Myers, K., Kataura, T., Korolchuk, V. I., Maddocks, O. D. K., Martins, L. M., Sanz, A. (2025). Developmental mitochondrial complex I activity determines lifespan. EMBO Rep, 26(8):1957-1983 PubMed ID: 40097814
Summary: Aberrant mitochondrial function has been associated with an increasingly large number of human disease states. Observations from in vivo models where mitochondrial function is altered suggest that maladaptations to mitochondrial dysfunction may underpin disease pathology. It was hypothesized that the severity of this maladaptation could be shaped by the plasticity of the system when mitochondrial dysfunction manifests. To investigate this,inducible fly models of mitochondrial complex I (CI) dysfunction were used to reduce mitochondrial function at two stages of the fly lifecycle, from early development and adult eclosion. In early life (developmental) mitochondrial dysfunction results in severe reductions in survival and stress resistance in adulthood, while flies where mitochondrial function is perturbed from adulthood, are long-lived and stress resistant despite having up to a 75% reduction in CI activity. After excluding developmental defects as a cause, this study on to molecularly characterize these two populations of mitochondrially compromised flies, short- and long-lived. The short-lived flies have unique transcriptomic, proteomic and metabolomic responses, which overlap significantly in discrete models of CI dysfunction. The data demonstrate that early mitochondrial dysfunction via CI depletion elicits a maladaptive response, which severely reduces survival, while CI depletion from adulthood is insufficient to reduce survival and stress resistance. |
| Cai, Q., Wang, Z., Xiao, Y., Zhang, C., Yang, Y., Kong, F., Feng, Y., Guo, H., Saeed, M. A. R., Ali, U., Li, W., Ji, S. (2025). MESR4 targets bam to mediate intestinal homeostasis and aging in adult flies. Insect Sci, PubMed ID: 39964140
Summary: The Drosophila melanogaster (fruit fly) misexpression suppressor of Ras 4 (MESR4) gene encodes a potential transcription factor and plays critical roles in various biological processes, including embryonic development, lipid metabolism, eye-antennal development, and germline stem cell differentiation. However, whether it is involved in modulating intestinal homeostasis remains elusive. This study provides compelling evidence demonstrating that MESR4 is a bona fide regulator in preventing age-onset intestinal leakage and dysbiosis in adult flies. Mechanistically, MESR4 is predominantly located at the nucleus of intestinal cells and controls the expression of bag-of-marbles (bam), thereby restricting the excessive activation of immune deficiency signaling during aging. The silencing of Relish (Rel), which encodes a key transcription factor of the immune deficiency signaling pathway, reverses the beneficial effects of MESR4 in mediating intestinal barrier function and fly lifespan. Collectively, our studies uncover an undescribed function of Drosophila MESR4 in the maintenance of intestinal homeostasis and overall organismal fitness. | Zhu, Y., Xiao, S., Guan, X., Deng, H., Ai, L., Fan, K., Xue, J., Li, G., Bi, X., Xiao, Q., Huang, Y., Jiang, L., Huang, W., Jin, P., Duan, R. (2025). Modulating CCTG repeat expansion toxicity in DM2 Drosophila model through TDP1 inhibition. EMBO Mol Med, 17(5):967-992 PubMed ID: 40133672
Summary: Myotonic dystrophy type 2 (DM2), caused by CCTG repeat expansion, is a common adult-onset disorder characterized by myotonia and progressive muscle degeneration with no effective treatment. This study, using a Drosophila model, identified Tyrosyl-DNA phosphodiesterase 1 (TDP1) as a novel modifier for DM2 therapeutic intervention through a high-throughput chemical screening of 2160 compounds. Moreover, both genetic and pharmacological inhibition of TDP1 translates to a cascade of beneficial effects, including improved motor functions, amelioration of progressive muscle degeneration, repair of muscle fiber damage, and normalization of aberrant molecular pathology. Remarkably, the TDP1 inhibition led to substantial CCTG repeat contractions, a mechanism that underlies the observed muscle toxicity and neurodegeneration. These results highlighted the potential of TDP1 as a molecular target for addressing the complex interplay between repeat expansions and neuromuscular degeneration in DM2, hinting at broader applicability in a spectrum of repeat expansion disorders. |
| Zhao, Y., Duan, J., van de Leemput, J., Han, Z. (2025). Cardiac neurons expressing a glucagon-like receptor mediate cardiac arrhythmia induced by high-fat diet in Drosophila bioRxiv, PubMed ID: 40161619
Summary: Cardiac arrhythmia leads to increased risks for stroke, heart failure, and cardiac arrest. Arrhythmic pathology is often rooted in the cardiac conduction system, but the mechanism is complex and not fully understood. For example, how metabolic diseases, like obesity and diabetes, increase the risk for cardiac arrhythmia. Glucagon regulates glucose production, mobilizes lipids from the fat body, and affects cardiac rate and rhythm, attributes of a likely key player. Drosophila is an established model to study metabolic diseases and cardiac arrhythmias. Since glucagon signaling is highly conserved, high-fat diet (HFD)-fed flies were used to study its effect on heart function. HFD led to increased heartbeat and an irregular rhythm. The HFD-fed flies showed increased levels of Adipokinetic hormone (Akh), the functional equivalent to human glucagon. Both genetic reduction of Akh and eliminating the Akh producing cells (APC) rescued HFD-induced arrhythmia, whereas heart rhythm was normal in Akh receptor mutants (AkhR(null)). Furthermore, a pair of cardiac neurons was discovered that express high levels of Akh receptor. These are located near the posterior heart, make synaptic connections at the heart muscle, and regulate heart rhythm. Altogether, this Akh signaling pathway provides new understanding of the regulatory mechanisms between metabolic disease and cardiac arrhythmia. | Sun, Y., Ma, H., Zhou, X., Huang, L., Yu, P., Qi, Y., Wei, G., Ni, T. (2024). Deficiency of Gut-Enriched Lipase H Promotes Gut Aging and Reduces Lifespan in Drosophila Phenomics, 4(6):531-547 PubMed ID: 40061826
Summary: Liph, a gut-enriched Lipase H encoding gene, shows decreased expression during gut aging in both fruit fly and mouse. However, whether such evolutionary conserved Liph plays a protective role in gut aging remains unknown. This study reports that knocking down CG6295, the Drosophila ortholog of the mammalian Liph, led to a shortened lifespan. Loss of CG6295 in adult fly whole body caused impaired gut integrity and function, as well as reduced gut lipid storage in Drosophila. Activation of the Toll/ immune deficiency (Imd) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) immune pathways, and the release of pro-inflammatory cytokineUpd3 (IL-6) indicated immune responses in CG6295 knockdown samples. What's more, knockdown of Drosophila CG6295 specifically in enterocytes (ECs) led to enlarged and flattened ECs, suggesting a potential regulatory mechanism of CG6295 in gut aging. In addition, down-regulation of Liph induced senescence-associated cellular and molecular phenotypes in a rat intestine cell model, suggesting the evolutionary conserved role of Liph in gut aging. Together, this study discovered Liph as a novel regulator for gut aging. |
Friday April 24th - Signaling |
| Kim, H., Little, J. C., Li, J., Patel, B., Kalderon, D. (2025). Hedgehog-stimulated phosphorylation at multiple sites activates Ci by altering Ci-Ci interfaces without full Suppressor of Fused dissociation. PLoS Biol, 23(4):e3003105 PubMed ID: 40215228
Summary: Hedgehog (Hh) proteins elicit dose-dependent transcriptional responses by binding Patched receptors to activate transmembrane Smoothened (Smo) proteins. Activated Smo inhibits Ci/Gli transcription factor phosphorylation by Protein Kinase A and consequent proteolytic processing to repressor forms; it also promotes nuclear transport and activity of full-length Ci/Gli proteins to induce Hh target genes. Smo-activated Fused (Fu) kinase drives Ci activation in Drosophila, while Suppressor of Fused (Su(fu)) counters full-length Ci/Gli activity and stabilizes full-length Ci/Gli by direct binding to at least three surfaces. This study used CRISPR-generated designer ci alleles to investigate alterations to Fu phosphorylation sites and to regions around Ci-Su(fu) interfaces under physiological conditions in Drosophila imaginal wing discs. Surprisingly, alterations were identified that activate Ci without significant loss of stabilization by Su(fu) and contributions of multiple Fu target sites to Ci activation in the absence of Su(fu), suggesting that the affected sites mediate Ci activation by regulating Ci-Ci, rather than Ci-Su(fu) interactions. It is proposed that those interactions maintain full-length Ci in a closed conformation that also facilitates, and is stabilized by, cooperative Ci-Su(fu) binding. Access to binding partners necessary for Ci activation is promoted through phosphorylation of at least four Fu sites on Ci, likely by directly disrupting Ci-Ci contacts and one Ci-Su(fu) interface without substantial Ci-Su(fu) dissociation, contrary to previous proposals. This study also found that the Ci binding partner, Costal 2 (Cos2), which silences Ci in the absence of Hh, can facilitate Ci activation by Fu kinase. | Aranjuez, G. F., Patel, O., Patel, D., Jewett, T. J. (2025). The N-terminus of the Chlamydia trachomatis effector Tarp engages the host Hippo pathway, Microbiol Spectr, 13(4):e0259624 PubMed ID: 40062849
Summary: Chlamydia trachomatis (Ct) is an obligate, intracellular Gram-negative bacteria and the leading bacterial sexually transmitted infection in the United States. Chlamydia manipulates the host cell biology using various secreted bacterial effectors during its intracellular development. The early effector translocated actin-recruiting phosphoprotein (Tarp), important for Chlamydia entry, has a well-characterized C-terminal region which can polymerize and bundle F-actin. In contrast, not much is known about the function of the N-terminus of Tarp (N-Tarp), though present in many Chlamydia spp. To address this, Drosophila melanogaster was used as an in vivo cell biology platform to study N-Tarp-host interactions. Transgenic expression of N-Tarp in Drosophila results in developmental phenotypes consistent with altered host Salvador-Warts-Hippo signaling, a conserved signaling cascade that regulates host cell proliferation and survival. The N-Tarp function was studied in larval imaginal wing discs, which are sensitive to perturbations in Hippo signaling. N-Tarp causes wing disc overgrowth and a concomitant increase in adult wing size, phenocopying overexpression of the Hippo co-activator Yorkie. N-Tarp also causes upregulation of Hippo target genes. Last, N-Tarp-induced phenotypes can be rescued by reducing the levels of Yorkie or the Hippo target genes CycE and Drosophila inhibitor of apoptosis 1 (Diap1). Thus, this study provides evidence that the N-terminal region of the Chlamydia effector Tarp is sufficient to alter host Hippo signaling and acts upstream of the co-activator Yorkie. |
| Yeom, E., Mun, H., Lim, J., Chun, Y. L., Min, K. W., Lambert, J., Cowart, L. A., Pierce, J. S., Ogretmen, B., Cho, J. H., Chang, J. H., Buchan, J. R., Pitt, J., Kaeberlein, M., Kang, S. U., Kwon, E. S., Ko, S., Choi, K. M., Lee, Y. S., Ha, Y. S., Kim, S. J., Lee, K. P., Kim, H. S., Yang, S. Y., Shin, C. H., Yoon, J. H., Lee, K. S. (2025). Phosphorylation of an RNA-Binding Protein Rck/Me31b by Hippo Is Essential for Adipose Tissue Aging. Aging Cell, 24(6):e70022 PubMed ID: 40070010 The metazoan lifespan is determined in part by a complex signaling network that regulates energy metabolism and stress responses. Key signaling hubs in this network include insulin/IGF-1, AMPK, mTOR, and sirtuins. The Hippo/Mammalian Ste20-like Kinase1 (MST1) pathway has been reported to maintain lifespan in Caenorhabditis elegans, but its role has not been studied in higher metazoans. This study reports that overexpression of Hpo, the MST1 homolog in Drosophila melanogaster, decreased lifespan with concomitant changes in lipid metabolism and aging-associated gene expression, while RNAi Hpo depletion increased lifespan. These effects were mediated primarily by Hpo-induced transcriptional activation of the RNA-binding protein maternal expression at 31B (Me31b)/RCK, resulting in stabilization of mRNA-encoding a lipolytic hormone, Akh. In mouse adipocytes, Hpo/Mst1 mediated adipocyte differentiation, phosphorylation of RNA-binding proteins such as Rck, decapping MRNA 2 (Dcp2), enhancer Of MRNA decapping 3 (Edc3), nucleolin (NCL), and glucagon mRNA stability by interacting with Rck. Decreased lifespan in Hpo-overexpressing Drosophila lines required expression of Me31b, but not DCP2, which was potentially mediated by recovering expression of lipid metabolic genes and formation of lipid droplets. Taken together, our findings suggest that Hpo/Mst1 plays a conserved role in longevity by regulating adipogenesis and fatty acid metabolism. | Huang, Y. T., Calvi, B. R. (2025). Activation of a Src-JNK pathway in unscheduled endocycling cells of the Drosophila wing disc induces a chronic wounding response. bioRxiv, PubMed ID: 40161657
Summary: The endocycle is a specialized cell cycle during which cells undergo repeated G / S phases to replicate DNA without division, leading to large polyploid cells. The transition from a mitotic cycle to an endocycle can be triggered by various stresses, which results in unscheduled, or induced endocycling cells (iECs). While iECs can be beneficial for wound healing, they can also be detrimental by impairing tissue growth or promoting cancer. However, the regulation of endocycling and its role in tissue growth remain poorly understood. Using the Drosophila wing disc as a model, we previously demonstrated that iEC growth is arrested through a Jun N-Terminal Kinase (JNK)-dependent, reversible senescence-like response. However, it remains unclear how JNK is activated in iECs and how iECs impact overall tissue structure. In this study, a genetic screen was performed, and he Src42A-Shark-Slpr pathway was identified as an upstream regulator of JNK in iECs, leading to their senescence-like arrest. Tissues recognize iECs as wounds, releasing wound-related signals that induce a JNK-dependent developmental delay. Similar to wound closure, this response triggers Src-JNK-mediated actomyosin remodeling, yet iECs persist rather than being eliminated. These findings suggest that the tissue response to iECs shares key signaling and cytoskeletal regulatory mechanisms with wound healing and dorsal closure, a developmental process during Drosophila embryogenesis. However, because iECs are retained within the tissue, they create a unique system that may serve as a model for studying chronic wounds and tumor progression. |
| Qian, W., Zhang, X., Yuan, D., Wu, Y., Li, H., Wei, L., Li, Z., Dai, Z., Song, P., Sun, Q., Zhou, Z., Xia, Q., Cheng, D. (2025). USP8 and Hsp70 regulate endoreplication by synergistically promoting Fzr deubiquitination and stabilization Sci Adv, 11(12):eadq9111 PubMed ID: 40106570
Summary: Endoreplication is characterized by multiple rounds of DNA replication without cell division and determines the growth and final size of endoreplicating cells and tissues in eukaryotes. The cyclic ubiquitination and degradation of several cell cycle regulators are required for endoreplication progression. However, the deubiquitinase that deubiquitinates and stabilizes key factors to modulate endoreplication remains unknown. This study found in the endoreplicating Drosophila salivary gland and Bombyx silk gland that the depletion of ubiquitin-specific peptidase 8 (USP8) led to endoreplication arrest and a decrease in gland size. Mechanistically, this study showed that USP8 interacted with the Fizzy-related (Fzr) protein, a conserved master regulator of endoreplication, thereby deubiquitinating and stabilizing Fzr to modulate endoreplication. Moreover, the molecular chaperone heat shock protein 70 (Hsp70) mediated proper folding of Fzr and increased the interaction between Fzr and USP8, thereby promoting the deubiquitination and stabilization of Fzr. Together, this study demonstrates that USP8 and Hsp70 regulate endoreplication by synergistically maintaining Fzr stability though deubiquitination. | Hsu, F. T., Smith-Bolton, R. (2025). Myc and Tor drive growth and cell competition in the regeneration blastema of Drosophila wing imaginal discs bioRxiv, PubMed ID: 40161768
Summary: During the regeneration of injured or lost tissues, the regeneration blastema serves as a hub for robust growth. Drosophila imaginal discs are a genetically tractable and simple model system for the study of regeneration and organization of this regrowth. Key signals that contribute to regenerative growth in these discs, such as ROS, Wnt/Wg, JNK, p38, JAK/STAT, and the Hippo pathway, have been identified. However, a detailed exploration of the spatial organization of regrowth, the factors that directly drive this growth, and the consequences of activating drivers of regeneration has not been undertaken. This study found that regenerative growth in imaginal discs is controlled by the transcription factor Myc and by Tor signaling, which additively drive proliferation and translation in the regeneration blastema. The spatial organization of growth in the blastema is arranged into concentric growth zones defined by Myc expression, elevated Tor activity, and elevated translation. In addition, the increased Myc expression in the innermost zone induced Xrp1-independent cell competition-like death in the adjacent zones, revealing a delicate balance between driving growth and inducing death in the regenerating tissue. |
Thursday April 23rd - Genes, RNAs, Enzynes and Proteins |
| Jeong, H., Son, S., Lee, G., Park, J. H., Yoo, S. (2025). Biogenesis of circular RNAs in vitro and in vivo from the Drosophila Nk2.1/scarecrow gene. G3 (Bethesda), 15(5) PubMed ID: 40071305
Summary: The scarecrow (scro) gene encodes a fly homolog of mammalian Nkx2.1, which is vital for early fly development and for optic lobe development. Previously, scro was reported to produce a circular RNA in addition to traditional mRNAs. This study report 12 different scro circular RNAs, which are either mono or multiexonic forms. The most abundant ones are circScro2) carrying the second exon (E2) only and bi-exonic circScro3,4 having both the third (E3) and fourth exon (E4). Levels of circScro2) show an age-dependent increase in adult heads, supporting a general trend of high accumulation of circular RNAs in aged fly brains. In silico analysis of the introns flanking circular RNA exons predicts 2 pairs of intronic complementary sequences; 1 pair residing in introns 1 and 2 and the other in introns 2 and 4. The first pair was demonstrated to be essential for the circScro2 production in cell-based assays; furthermore, deletion of the region including intronic complementary sequence components in the intron-2 reduces in vivo production of both circScro2 and circScro3,4 by 80%, indicating them to be essential for the biogenesis of the 2 circular RNAs. Besides the intronic complementary sequence, the intron regions immediately abutting exons seem to be responsible for a basal level of circular RNA formation. Moreover, ectopic intronic complementary sequence derived from the laccase2 locus is comparably effective in circScro production, buttressing the importance of the hairpin loop structure formed by intronic complementary sequence for the biogenesis of circular RNA. Last, overexpressed scro alters outcomes of both linear and circular RNAs from the endogenous scro locus, suggesting that Scro plays a direct or indirect role in regulating the expression levels of either or both forms. | Ito, R., Ojima, H., Takebayashi, M., Takeuchi, M., Takahashi, H., Mori, S., Ihara, M., Sattelle, D. B., Matsuda, K. (2025). Binding site loops D and G make a stronger contribution than loop C to the actions of neonicotinoids on the NACHO-assisted, robustly expressed Drosophila melanogaster Dα1/Dβ1 nicotinic acetylcholine receptor. Pestic Biochem Physiol, 209:106325 PubMed ID: 40082022
Summary: TMX3 is essential for the functional expression of insect nicotinic acetylcholine receptors (nAChRs) and RIC-3 and mpeding H3K9me2 spreading. In addition to these cofactors, NACHO has been shown to enhance functional expression of certain vertebrate nAChRs and an insect homomeric nAChR. This study has examined the impact of Drosophila melanogaster NACHO (DmNACHO) on the ACh-induced response amplitude of the fruit fly Dα1Dβ1 nAChRs coexpressed in Xenopus laevis oocytes with DmRIC-3, DmTMX3 and DmUNC-50 and examined the actions of neonicotinoid insecticides. DmNACHO markedly enhanced the ACh and neonicotinoid-induced response amplitude of Dα1/Dβ1 nAChRs coexpressed with the three cofactors DmRIC-3, DmTMX3 and DmUNC-50, while scarcely influencing ligand affinity. Given the robust Dα7alpha;1/Dβ1 nAChR expression with the aid of the four cofactors, this study investigated the impact of mutations in loops C, D and G of the orthosteric ligand binding domain (LBD) on the actions of the neonicotinoids imidacloprid and thiacloprid. Both the R81T mutation in loop D and the A60S mutation in loop G significantly reduced the agonist actions of the neonicotinoids, whereas the S221E mutation in loop C had no significant effect on agonist actions on this nAChR. Further, no greater affinity and efficacy reducing effects were observed even when the S221E mutation in loop C was combined with the R81T mutation in loop D, the A60S mutation in loop G, or both, demonstrating that loop D and loop G are more critical than loop C in determining the target-site actions of imidacloprid and thiacloprid. |
| Yan, Y., Zhao, J., Schwirz, J., Borghesi, C., Liu, C., Liu, B., Qian, W., Wan, F., Schetelig, M. F. (2025). The transformer gene controls sexual development in Drosophila suzukii Insect Sci, PubMed ID: 40159710
Summary: The genetic network of sex determination in the model organism Drosophila melanogaster was investigated in great detail. Such knowledge not only advances understanding of the evolution and regulation of sexual dimorphism in insects, but this study serves as a basis for developing genetic control strategies for pest species. This study, isolated the sex determination gene transformer (Dstra) from a global fruit pest, the spotted-wing Drosophila (Drosophila suzukii), and characterized its gene organization. By comparing the deduced protein sequence of Dstra with its orthologs from 22 species, it was found that tra genes from Dipteran species are divergent. This research demonstrated that Dstra undergoes sex-specific splicing, and its developmental expression profile was validated. A piggyBac-based transformation vector expressing the complete Dstra coding sequence was engineered under the control of the Tetracycline-Off system. Through germ-line transformation, 4 independent transgenic lines were generated, producing pseudo-females from chromosomal males in the absence of tetracycline. This observation indicated ectopic expression of Dstra, confirmed by the detection of female Dstra transcripts in transgenic males. The pseudo-females exhibited altered wing patterns, feminized abdomen, abnormal reproductive organs, and disrupted sexual behavior. Ectopic expression of Dstra affected the sex-specific splicing pattern of the downstream gene fruitless, but not doublesex. In conclusion, this study provides comprehensive genetic, morphological, and behavioral evidence that Dstra controls sexual development in D. suzukii. The potential applications of this research for genetic control strategies targeting Dstra or using its gene elements is discussed. | Parada, C., Prieto, D. (2025). Survival, Movement, and Lifespan: Decoding the Roles of Patched-Related in Drosophila melanogaster Arch Insect Biochem Physiol, 118(3):e70048 PubMed ID: 40070106
Summary: Patched-related (Ptr) is a transmembrane protein implicated in developmental processes in Drosophila melanogaster, yet its precise role remains incompletely understood. This study use Ptr23c) null mutants to investigate the functional significance of Ptr through the entire life cycle monitoring survival during embryonic, larval, pupal and adult development, and studying larval locomotion and muscle structure. Ptr23c larvae displayed impaired hatching, indicative of defective embryonic development. Moreover, mutant larvae exhibited reduced mobility and lethargy, suggesting a potential involvement of Ptr in neuromuscular function. Morphological analysis of somatic muscles in mutant larvae revealed enlarged cell nuclei. Despite high preadult mortality, a subset of Ptr23c mutant adults display an unexpected extension in lifespan compared to controls, implicating Ptr in the regulation of longevity. These findings provide critical insights into the multifaceted role of Ptr in Drosophila development, highlighting its contributions to post-embryonic survival, neuromuscular function, and lifespan regulation. This study underscores the significance of exploring broader genetic networks to unravel the complexities of developmental processes. |
| Jin, Z., Meng, Z., Liu, Y., Li, C., Zhang, X., Yin, Y., Gao, G., Dou, K., Huang, Y. (2025). Structural basis of thymidine-rich DNA recognition by Drosophila P75 PWWP domain Commun Biol, 8(1):445 PubMed ID: 40089621
Summary: Drosophila P75 [JIL-1 anchoring and stabilizing protein (dP75)], a homolog of the human LEDGF/p75, is crucial for oogenesis by recruiting the histone kinase Jil-1 to euchromatin and impeding H3K9me2 spreading. Like LEDGF, dP75 binds transcriptionally active chromatin, but its precise mechanism remains unclear. This study shows that its PWWP domain prefers binding to thymidine-rich DNA over GC-rich sequences. Crystal structures both in apo and ssDNA-bound states, reveal a domain-swapped homodimer. The aromatic cage, known to recognize histone methyllysine, also engages thymine. Mutations in this cage mimic dP75 knockout phenotypes, including impaired chromatin binding, transposon upregulation, and female sterility. Although dP75 maintains chromatin-bound in H3K36A mutant flies, alterations in the aromatic cage disrupt this localization, underscoring its role in DNA binding. These findings reveal how dP75 targets euchromatin through a PWWP domain that integrates histone reading and nucleotide recognition, advancing understanding of PWWP domains. | Hu, L., Wainman, A., Andreeva, A., Apizi, M., Alvarez-Rodrigo, I., Wong, S. S., Saurya, S., Sheppard, D., Cottee, M., Johnson, S., Lea, S. M., Raff, J. W., van Breugel, M., Feng, Z. (2025). The conserved Spd-2/CEP192 domain adopts a unique protein fold to promote centrosome scaffold assembly Sci Adv 21;11(12):eadr5744. PubMed ID: 40106572
Summary: Centrosomes form when centrioles assemble pericentriolar material (PCM) around themselves. Spd-2/CEP192 proteins, defined by a conserved "Spd-2 domain" (SP2D) comprising two closely spaced AspM-Spd-2-Hydin (ASH) domains, play a critical role in centrosome assembly. This study shows that the SP2D does not target Drosophila spd-2 to centrosomes but rather promotes PCM scaffold assembly. Crystal structures of the human and honeybee SP2D reveal an unusual "extended cradle" structure mediated by a conserved interaction interface between the two ASH domains. Mutations predicted to perturb this interface, including a human mutation associated with male infertility and Mosaic Variegated Aneuploidy, disrupt PCM scaffold assembly in flies. The SP2D is monomeric in solution, but the Drosophila SP2D can form higher-order oligomers upon phosphorylation by PLK1 (Polo-like kinase 1). Crystal-packing interactions and AlphaFold predictions suggest how SP2Ds might self-assemble, and mutations associated with one such potential dimerization interface markedly perturb SP2D oligomerization in vitro and PCM scaffold assembly in vivo. |
Wednesday April 22nd - Immune Response |
| Qush, A., Yassine, H. M., Zeidan, A., Kamareddine, L. (2025). Diet-induced mechanical stress promotes immune and metabolic alterations in the Drosophila melanogaster digestive tract J Invertebr Pathol, 211:108348 PubMed ID: 40320046
Summary: A fundamental query in immunology is how cells recognize danger in the tissue milieu. For many years, standpoints were mainly centered around damaged cells or structures of invading pathogens, like lipopolysaccharide, being the initiators of danger signals to activate immunity. Today, rising evidence presents "biophysical signals" as potential regulators of immune cell function too. This emerging notion of the ability of tissue mechanotransduction to tune the immunological system appears to likewise exist in other body system, among which is the metabolic system, where startling connection between mechanotransduction and enzymes known to regulate metabolism have been also reported. Being continuously subjected to mechanical forces, and owing to its multifaceted role in not only absorbing and digesting nutrients, but also in supporting important immunological defense strategies as well as metabolic responses, attention has been lately given to organs making up the gastrointestinal (GI) tract, predominantly the intestine, with growing interest in unravelling the impact of mechanotransduction on the intestinal environment is on the rise. As such, we investigated in this study the impact of mechanical stress introduced by ingesting diet containing the indigestible fiber methylcellulose (MC) on gut immune and metabolic activities using the Drosophila melanogaster model organism. Our findings reveal that feeding on MC-containing diet causes consequential alterations in the fly gut environment manifested by enlargement of the midgut diameter, remodeling of the microbiota community, activation of immune responses, differential regulation of the tachykinin (Tk) peptide hormone expression and modulation of lipometabolism. Particularly, we show that feeding on MC-containing diet promotes a marked increase in the relative abundance of Leuconostocaceae/Leuconostoc, microbiota-dependent Reactive Oxygen Species (ROS) production, IMD pathway activation, and IMD-dependent elevation in Tk expression. We also demonstrate that maintaining flies on MC-containing diet for several days leads to a reduction in body weight and in systemic glucose and triacylglycerol levels and modulates lipid droplets accumulation and storage in the gut and fat body. Taken together, these findings provide novel insight into the effect of diet induced-mechanical forces on the intestinal physiology and pathology. | Kachaev, Z. M., Ghassah, M., Musabirov, A. A., Shaposhnikov, A. V., Toropygin, I. Y., Ulianova, Y. A., Stepanov, N. G., Chmykhalo, V. K., Shidlovskii, Y. V. (2025). The Enhanced activation of innate immunity in Drosophila S2 cells by Micrococcus luteus VKM Ac-2230 is mediated by Relish, J Invertebr Pathol, 211:108315 PubMed ID: 40089097
Summary: The canonical model of immune response activation in Drosophila suggests that the IMD pathway is activated by Gram-negative (Gram (-)) bacteria, while the Toll pathway is activated by both Gram-positive bacteria (Gram (+)) and fungi. However, the mechanisms by which these pathogens promote cross-activation of these pathways remain controversial. In addition, the mechanisms of cross-activation in S2 cell culture remain unstudied. This study investigated the role of two Gram (+) bacteria (Micrococcus luteus and Bacillus subtilis) and fungal spores (Metarhizium anisopliae) in activating the IMD pathway in S2 cell cultures. Cells were treated with Escherichia coli as a control to ensure the specificity of IMD pathway activation. The results demonstrated a significant involvement of M. luteus in the activation of the IMD pathway in S2 cell cultures. This is evidenced by the marked activation of IMD pathway-dependent genes, as well as the proteolytic cleavage of the Relish protein, which serves as a key transcription factor for this pathway. We also observed a strong recruitment of Relish to the promoters of antimicrobial peptide (AMP) genes, along with a partial recruitment to the genes encoding peptidoglycan recognition proteins (PGRPs). Furthermore, RNA interference targeting Relish resulted in a significant reduction in the transcription levels of all AMP genes and most PGRPs. Similarly, we analyzed the contributions of B. subtilis and M. anisopliae to the cross-activation of the IMD pathway. Our data indicate that both B. subtilis and M. anisopliae also activate the IMD pathway, albeit to a lesser extent compared to M. luteus. At the same time, fungal spores exhibited minimal influence on the activation of the IMD pathway when compared to Gram (+) bacteria. Thus, we have investigated in detail the mechanisms of cross-activation of the immune response in S2 cell culture, suggesting that Relish may play a critical role in inducing a humoral immune response in Drosophila S2 cells, primarily against M. luteus and to a lesser extent against B. subtilis and M. anisopliae. |
| Wu, C., Chen, Y., Zheng, C., Huang, X., Xie, Y., Lin, L., Zhang, X., Xie, L. (2025). The Role of AaPGRP-LB in the Immune Response of Aedes albopictus Against Bacteria Infection. Int J Mol Sci, 26(5) PubMed ID: 40076812
Summary: The initial phase of an insect's innate immune response to foreign pathogens is triggered by the identification of exogenous invaders, a mechanism facilitated by pattern recognition receptors. Among these receptors, peptidoglycan recognition proteins (PGRPs), abundant in insects, are essential components of the innate immune system. The roles of PGRPs have been extensively elucidated in Drosophila melanogaster; however, the mechanism underlying the immune response of Aedes albopictus to pathogens is unclear. This study successfully cloned the full-length cDNA of a PGRP gene from Ae. albopictus, designated as the AaPGRP-LB gene (see Drosophila PGRP-LB). The open reading frame of AaPGRP-LB encodes 203 amino acids, including a secretion signal peptide and a canonical PGRP conserved domain. Multisequence alignment revealed that AaPGRP-LB possesses the amino acid residues essential for zinc binding and amidase activity. Molecular docking studies demonstrated that AaPGRP-LB exhibits a strong binding affinity for DAP-type and LYS-type peptidoglycan. The mRNA expression level of the AaPGRP-LB gene significantly increased after oral infection with Escherichia coli or Staphylococcus aureus. The purified recombinant AaPGRP-LB (rAaPGRP-LB) exhibited strong agglutination properties and demonstrated significant antimicrobial efficacy against E. coli and S. aureus in the presence of zinc ions. This study highlights the critical role of AaPGRP-LB in the immune response of Ae. albopictus. These findings provide a foundation for future research on mosquito immune pathways for innovative vector control and disease prevention strategies. | Zhang, C., Zhou, C., He, L., Yang, H., Ding, B., Smagghe, G., Yang, M. (2025). Identification and characterization of Spatzle in Myzus persicae and its role during microbial infection. Insect Sci, PubMed ID: 40229966
Summary: As a Toll receptor ligand, Spatzle (Spz) plays a crucial role in activating the Toll pathway and participating in the innate immune response of insects. However, the immune function of Spz in Myzus persicae remains poorly understood. This study identified and cloned 7 Spz genes from M. persicae, all containing a Spz domain (cystine-knot domain). Phylogenetic analysis revealed that the 7 different MpSpzs were divided into 6 groups within a single cluster with each Spz of Drosophila melanogaster and Acyrthosiphon pisum. These genes were mainly expressed in 1st-instar nymphs, hemolymph, and embryos and showed varying levels of positive response to infection with Escherichia coli, Staphylococcus aureus, and Beauveria bassiana. After gene-silencing of MpSpzs by RNA interference with injection of target gene-specific double-stranded RNA, microbial infection significantly increased the mortality of M. persicae compared to control groups. Further studies revealed that the suppression of MpSpz resulted in a significant reduction in lysozyme expression. The present study offers novel insights into the role of Spatzle in the innate immune response against microbial infection in M. persicae. |
| Duan, R., Hu, B., Ding, E., Zhang, S., Wu, M., Jin, Y., Ali, U., Saeed, M. A. R., Raza, B., Usama, M., Batool, S. S., Cai, Q., Ji, S. (2025). Cul2 Is Essential for the Drosophila IMD Signaling-Mediated Antimicrobial Immune Defense. Int J Mol Sci, 26(6) PubMed ID: 40141268
Summary: Cullin 2 (Cul2), a core component of the Cullin-RING E3 ubiquitin ligase complex, is integral to regulating distinct biological processes. However, its role in innate immune defenses remains poorly understood. This study investigated the functional significance of Cul2 in the immune deficiency (IMD) signaling-mediated antimicrobial immune reactions in Drosophila melanogaster (fruit fly). Loss-of-function of Cul2 led to a marked reduction in antimicrobial peptide induction following bacterial infection that was associated with increased fly mortality and bacterial load. The proteomic analysis further revealed that loss-of-function of Cul2 reduced the expression of Effete (Eff), a key E2 ubiquitin-conjugating enzyme during IMD signaling. Intriguingly, ectopic expression of eff effectively rescued the immune defects caused by loss of Cul2. Taken together, the results of this study underscore the critical role of Cul2 in ensuring robust IMD signaling activation, highlighting its importance in the innate immune defense against microbial infection in Drosophila. | Rommelaere, S., Schupfer, F., Armand, F., Hamelin, R., Lemaitre, B. (2025). An updated proteomic analysis of Drosophila haemolymph after bacterial infection. Fly (Austin), 19(1):2485685 PubMed ID: 40223358
Summary: Using an in-depth Mass Spectrometry-based proteomics approach, this study provided a comprehensive characterization of the hemolymphatic proteome of adult flies upon bacterial infection. Changes in abundance of several known immune regulators and effectors were detected and quantified including multiple antimicrobial peptides, peptidoglycan-binding proteins and serine proteases. Comparison to previously published transcriptomic analyses reveals a partial overlap with the current dataset, indicating that many proteins released into the haemolymph upon infection may not be regulated at the transcript level. Among them, a set of muscle-derived proteins released into the haemolymph upon infection were identified. Finally, the analysis reveals that infection induces major changes in the abundance of proteins associated with mitochondrial respiration. This study uncovers a large number of previously undescribed proteins potentially involved in the immune response. |
Tuesday April 21st - RNA and Transposons |
| Varghese, L. N., Sheard, P. W., Schwenke, D. O., Katare, R. (2025). Sex-specific dysregulation of cardiac-enriched microRNAs with age in Drosophila melanogaster Am J Physiol Cell Physiol, 328(6):C1743-c1751 PubMed ID: 40250483
Summary: Dysregulation of cardiac-enriched microRNA (miRNA) expression is linked to age-associated cardiovascular diseases (CVDs). However, the sex-specificity and age at which dysregulation occurs remain unclear. Given the conserved nature of miRNAs and short lifespan of Drosophila melanogaster, this study investigated age-related changes in the expression of cardiac enriched miRNAs (miR-1, -9, -34a, and -133, target miRNAs) and their impact on the cardiac tube in male and female flies. Cardiac tube tissues were collected from male and female flies (n = 5/group) at 7-day intervals from day 7 to day 70. miRNAs and predicted target mRNA gene (KCNQ, MRTF, and CCN) expression were quantified by RT-qPCR. Myofibril diameter was assessed by Masson's trichrome staining (n = 4-6) to determine the structural effects of hypertrophic miR-9. In females, miR-1 was downregulated with age (P ≤ 0.0001), whereas in males, miR-9(P ≤0.0001) and mir-34 (P = 0.0017) were downregulated. Interestingly, miR-133 was downregulated in both sexes (P ≤ 0.0001). In males, MRTF (miR-9 target) and CCN (miR-133 target) expression increased with age (P = 0.016 and P = 0.013, respectively), whereas in females, KCNQ (miR-1 target) and CCN expression decreased (P = 0.03 and P = 0.002, respectively). Myofibril thickness significantly increased with age in both sexes (P <: 0.0001). miR-9 downregulation may contribute to this effect in males, whereas the mechanism in females remains unclear. This study provides novel insights into sex-specific miRNA dysregulation in cardiac aging, emphasizing the need to consider sex differences in miRNA-mediated cardiovascular aging and the potential of miRNAs as diagnostic tools in age-related CVDs. | Huang, Y., Gao, Z. Y., Ly, K., Lin, L., Lambooij, J. P., King, E. G., Janssen, A., Wei, K. H., Lee, Y. C. G. (2025). Polymorphic transposable elements contribute to variation in recombination landscapes Proc Natl Acad Sci U S A, 122(12):e2427312122 PubMed ID: 40100633
Summary: Meiotic recombination is a prominent force shaping genome evolution, and understanding why recombination rates vary within and between species has remained a central, though challenging, question. Variation in recombination is widely thought to influence the efficacy of selection in purging transposable elements (TEs), prevalent selfish genetic elements, leading to widely observed negative correlations between TE abundance and recombination rates across taxa. However, accumulating evidence suggests that TEs could instead be the cause rather than the consequence of this relationship. To test this prediction, this study formally investigated the influence of polymorphic, putatively active TEs on recombination rates. an approach that uses PacBio long-read sequencing to efficiently, accurately, and cost-effectively identify crossovers (COs), a key recombination product, among large numbers of pooled recombinant individuals. By applying this approach to Drosophila strains with distinct TE insertion profiles, this study found that polymorphic TEs, especially RNA-based TEs and TEs with local enrichment of repressive marks, reduce the occurrence of COs. Such an effect leads to different CO frequencies between homologous sequences with and without TEs, contributing to varying CO maps between individuals. The suppressive effect of TEs on CO is further supported by two orthogonal approaches-analyzing the distributions of COs in panels of recombinant inbred lines in relation to TE polymorphism and applying marker-assisted estimations of CO frequencies to isogenic strains with and without transgenically inserted TEs. Our investigations reveal how the constantly changing TE landscape can actively modify recombination, shaping genome evolution within and between species. |
| Preussner, M., Bischoff, M., Onel, S. F. (2025). mir-276a Is Required for Muscle Development in Drosophila and Regulates the FGF Receptor Heartless During the Migration of Nascent Myotubes in the Testis. Cells, 14(5) PubMed ID: 40072096
Summary: MicroRNAs function as post-transcriptional regulators in gene expression and control a broad range of biological processes in metazoans. The formation of multinucleated muscles is essential for locomotion, growth, and muscle repair. microRNAs have also emerged as important regulators for muscle development and function. In order to identify new microRNAs required for muscle formation, a large microRNA overexpression screen was perfored. Screening was oerformed for defects during embryonic and adult muscle formation. This study describes the identification of mir-276a as a regulator for muscle migration during testis formation. The mir-276a overexpression phenotype in testis muscles resembles the loss-of-function phenotype of heartless. A GFP sensor assay reveals that the 3'UTR of heartless is a target of mir-276a. Furthermore, mir-276a was found to be essential for the proper development of indirect flight muscles, and a method is describe for determining the number of nuclei for each of the six longitudinal muscle fibers (DLMs), which are part of the indirect flight muscles. | Taira, Y., Zhu, L. and Fukunaga, R. (2025). RNA-binding protein Miso/CG44249 is crucial for minor splicing during oogenesis in Drosophila Rna, 31(6):822-835 PubMed ID: 40169226
Summary: Pre-mRNA introns are removed by two distinct spliceosomes: the major (U2-type) spliceosome, which splices over 99.5% of introns, and the minor (U12-type) spliceosome, responsible for a rare class of introns known as minor introns. While the major spliceosome contains U1, U2, U4, U5, and U6 small nuclear RNAs (snRNAs) along with numerous associated proteins, the minor spliceosome comprises U11, U12, U4atac, U5, and U6atac snRNAs and includes specialized proteins. The function and regulation of the minor spliceosome are critical. Mutations in its specific component, RNA-binding protein RNPC3/65K, are linked to human diseases such as primary ovarian insufficiency. This study identified RNA-binding protein Miso (CG44249), which shares 31% and 27% amino acid sequence identity with human RNPC3 and RBM41, respectively, as a key factor in minor splicing and oogenesis in Drosophila Miso associates with U11 and U12 snRNAs in ovaries. miso mutant females exhibit smaller ovaries, reduced germline stem cell numbers, disrupted oogenesis, reduced fecundity, and lower fertility. In miso mutant ovaries, significant minor intron retention is observed, accompanied by a reduction in spliced RNAs and protein products. These findings establish Miso as a critical factor for minor intron splicing and underscore its essential role in Drosophila oogenesis. |
| Wharton, T. H., Marhabaie, M., Wharton, R. P. (2025). Significant roles in RNA-binding for the amino-terminal regions of Drosophila Pumilio and Nanos PLoS Genet, 21(3):e1011616 PubMed ID: 40163518
Summary: The Drosophila Pumilio (Pum) and Nanos (Nos) RNA-binding proteins govern abdominal segmentation in the early embryo, as well as a variety of other events during development. They bind together to a compound Nanos Response Element (NRE) present in thousands of maternal mRNAs in the ovary and embryo, including hunchback (hb) mRNA, thereby regulating poly-adenylation, translation, and stability. Many studies support a model in which mRNA recognition and effector recruitment are carried out by distinct regions of each protein. The well-ordered Pum and Nos RNA-binding domains (RBDs) are sufficient to specifically recognize NREs; the larger intrinsically disordered N-terminal regions (NTRs) of each protein have been thought to act by recruiting mRNA regulators. This study used yeast interaction assays and experiments testing the regulation of hb mRNA in vivo to show that the NTRs play a significant role in recognition of the NRE, acting via two mechanisms. First, the Pum and Nos NTRs interact in trans to promote assembly of the Pum/Nos/NRE ternary complex. Second, the Pum NTR acts via an unknown mechanism in cis, modifying NRE recognition by its RBD. The ability of the NTR to alter binding to the NRE is conserved in human Pum2. | Voichek, M., Bernhard, A., Novatchkova, M., Handler, D., Moseneder, P., Rafanel, B., Duchek, P., Senti, K. A., Brennecke, J. (2025). Direct cell-to-cell transmission of retrotransposons bioRxiv, PubMed ID: 40161635
Summary: Transposable elements are abundant in host genomes but are generally considered to be confined to the cell in which they are expressed, with the notable exception of endogenous retroviruses.This study identify a group of LTR retrotransposons that infect the germline from somatic cells within the Drosophila ovary, despite lacking the fusogenic Envelope protein typically required for retroviral entry. Instead, these elements encode a short transmembrane protein, sORF2, with structural features reminiscent of viral cell-cell fusogens. Through genetics, imaging, and electron microscopy, this study showed that sORF2 localizes to invasive somatic protrusions, enabling the direct transfer of retrotransposon capsids into the oocyte. Remarkably, sORF2-like proteins are widespread among insect retrotransposons and also occur in piscine nackednaviruses and avian picornaviruses. These findings reveal a noncanonical, Envelope-independent transmission mechanism shared by retrotransposons and non-enveloped viruses, offering important insights into host-pathogen evolution and soma-germline interactions. |
Friday April 17th - Adult Physiology and Metabolism |
| Wang, S., Zhou, S., Jiang, X., Yang, D., He, J., Xiu, M. (2025). Acute hypoxia induces sleep disorders via sima/HIF-1alpha regulation of circadian rhythms in adult Drosophila Comp Biochem Physiol C Toxicol Pharmacol, 294:110192 PubMed ID: 40086680
Summary: The atmospheric oxygen concentration is significantly reduced in highland regions compared to lowland areas. The first entering the plateau can induce sleep disorders in individuals, primarily attributed to insufficient oxygen supply. This study used Drosophila melanogaster as a model organism to better understand the molecular mechanism of acute hypoxia-induced sleep disorders. The Drosophila activity monitoring system (DAMS) was employed to observe the sleep-wake in adult (w(1118), sima/a>(KG07607), and clock(jrk)) female flies. Quantifying the relative mRNA expression levels of sima and circadian clock genes in the head of flies was accomplished by utilizing qRT-PCR. Acute hypoxia caused sleep disorders in w(1118) flies, such as shortened sleep duration and length, and prolonged sleep latency. PCR results showed that sima and clock genes were up-regulated in ZT6 and ZT12 and down-regulated in ZT0 and ZT18 in acute hypoxic w(1118) flies compared to normoxic w(1118) flies. Under normoxic conditions, sleep indexes in sima(KG07607) flies were not substantially different from w(1118) flies. However, clock(jrk) flies demonstrated a reduced sleep duration, decreased sleep bout length, and increased sleep latency and activities. Sleep and gene expression in sima(KG07607) flies under acute hypoxic conditions were not significantly different from those under normoxic conditions. Surprisingly, sleep and gene expression in clock(jrk) flies showed opposite trends to w(1118) flies. The present study indicates that acute hypoxia disrupt circadian rhythms through the activation of sima/HIF-1α, leading to the onset of sleep disorders, with Clock signaling potentially serving as a contributing factor. | Tesoriere, G., Pilesi, E., De Rosa, M., Giampaoli, O., Patriarca, A., Spagnoli, M., Chiocciolini, F., Tramonti, A., Contestabile, R., Sciubba, F., Verni, F. (2025). Vitamin B6 deficiency produces metabolic alterations in Drosophila Metabolomics, 21(2):42 PubMed ID: 40123014
Summary: Pyridoxal 5'-phosphate (PLP), the biologically active form of vitamin B6 is involved in 4% of cellular enzymatic activities and its deficiency is responsible for or contributes to several human diseases. The study of underlying mechanisms is still in its infancy and requires suitable model organisms. In Drosophila the deficiency of vitamin B6 produces chromosome aberrations and hallmarks of human diseases including diabetes and cancer. However, the effects of vitamin B6 deficiency have never been examined at a metabolic level. This study evaluates the metabolic changes in vitamin B6 deficient Drosophila larvae with the aim of validating flies as a suitable model for diseases associated to vitamin B6 deficiency. To induce vitamin B6 deficiency Drosophila wild type larvae were fed with 4-deoxypyridoxine (4DP), a PLP antagonist. By HPLC analysis this study verified that the 4DP treatment was effective in inducing vitamin B6 deficiency. Using an NMR-based metabolomic approach the metabolites in larval extracts were compared from untreated and 4DP-fed larvae. The NMR spectra analysis identified quantitative differences for sixteen metabolites out of forty, including branched chain and aromatic amino acids, glucose, and lipids, thus revealing interesting possible associations with the phenotypes showed by vitamin B6 deficient flies. These results validate Drosophila as a suitable model to study in depth the molecular mechanisms underlying human diseases associated with vitamin B6 deficiency and confirmed that 4DP treatment is effective in inducing vitamin B6 deficiency. |
| Basu, A., Singh, A., Prasad, N. G. (2025). Timing of starvation determines its effects on susceptibility to bacterial infection in female fruit flies independent of host evolutionary history. J Insect Physiol, 162:104794 PubMed ID: 40096990
Summary: An organism's susceptibility to pathogens is contingent on various environmental factors, including the availability of nutrition. Starvation can alter host susceptibility to infections, either directly via depletion of resources essential for proper functioning of the immune system, or indirectly via the various physiological changes it induces within the host body. This study tested if the susceptibility of Drosophila melanogaster populations to Enterococcus faecalis infection is interactively affected by (a) whether the hosts are starved before or after the infection, and (b) the evolutionary history of the host. Hosts from laboratory fly populations that have been experimentally evolved to be more resistant to E. faecalis, and their corresponding control populations, were subjected to infection with or without being starved prior to and after being infected. This study found that the effect of starvation on susceptibility to E. faecalis changed with the timing of starvation: starvation after infection improved survival of infected hosts, irrespective of how they were treated before infection, while starving only prior to infection (and not after) compromised post-infection survival. The changes in infection susceptibility were uniform in both the evolved and the control populations, suggesting that the effects of starvation are not dependent on pre-existing resistance to the infecting pathogen. | Nair, A., Mayekar, H. V., Sharma, M. D., Garg, D., Mitchell, C., Hosken, D. J., Rajpurohit, S. (2025). High altitude favours long-chained cuticular hydrocarbons in Drosophila. J Evol Biol, 38(5):606-617 PubMed ID: 40110846
Summary: Cuticular hydrocarbons (CHCs) are key components of the insect cuticle and contribute to the wide geographical distribution of this taxon. Many studies have investigated sex and population differences in CHC profiles, with these investigations mostly focusing on latitudinal CHC variation, whereas CHC variation across altitudinal transects is less well-studied. This study tested whether CHC profiles vary along an altitudinal gradient in the cosmopolitan vinegar fly Drosophila melanogaster. Collections were performed from three populations of D. melanogaster in the Western Himalayas at altitudes ranging from 760 to 2,592 m above sea level, and their CHC profiles were tested for standing and plastic variation. Quantitative differences were found in 25 CHCs across populations, and at higher elevations, males and females expressed higher amounts of particular long-chained hydrocarbons. Plastic shifts were found in CHC profiles in all three populations when flies were exposed to desiccating conditions. Overall, these findings suggest that there is an altitudinal cline in CHCs. However, this does not mirror the well-established latitudinal clines in fly hydrocarbons. |
| Meyer, C., Paululat, A. (2025). Valve cells are crucial for efficient cardiac performance in Drosophila PLoS Genet, 21(3):e1011613 PubMed ID: 40112281
Summary: Blood flow in metazoans is regulated by the activity of the heart. The open circulatory system of insects consists of relatively few structural elements that determine cardiac performance via their coordinated interplay. One of these elements is the intracardiac valve between the aorta and the ventricle. In Drosophila, it is built by only two cells, whose unique histology represents an evolutionary novelty. While the development and differentiation of these highly specialised cells have been elucidated previously, their physiological impact on heart performance is still unsolved. The present study investigated the physiological consequences of cardiac valve malformation in Drosophila. Cardiac performance is reduced if valves are malformed or damaged. Less blood is transported through the heart proper, resulting in a decreased overall transport capacity. A reduced luminal opening was identified as a main reason for the decreased heart performance in the absence of functional valves. Intracardiac hemolymph flow was visualised at the valve region by microparticle injection and revealed characteristic similarities to valve blood flow in vertebrates. Based on these data, a model is proposed on how the Drosophila intracardiac valves support proper hemolymph flow and distribution, thereby optimising general heart performance. | Hadjisavva, M. E., Cooper, R. L. (2025). The Biphasic Effect of Lipopolysaccharide on Membrane Potential Membranes (Basel), 15(3) PubMed ID: 40137026
Summary: Lipopolysaccharide (LPS) from certain strains of Gram-negative bacteria can induce a rapid (<1 s) hyperpolarization of membrane potential, followed by a gradual depolarization exceeding the initial resting membrane potential. Through overexpression of a Drosophila ORK1 two-pore-domain K(+) channel (K2P) in larval muscles and altering the external concentrations of K(+) and Na(+) ions, it is clear that the hyperpolarization is due to activating K2P channels and the depolarization is due to promoting an inward Na(+) leak. When the external Na(+) concentration is negligible, the LPS-delayed depolarization is dampened. The hyperpolarization induced by LPS can exceed -100 mV when external K(+) and Na(+) concentrations are lowered. These results indicate direct action by LPS on ion channels independently of immune responses. Such direct actions may need to be considered when developing clinical treatments for certain forms of bacterial septicemia. |
Thursday April 16th - Behavior |
| Rakosy, E., Talagala, S., Long, T. A. F. (2025). On the use of kinship and familiarity associated social information in mediating Drosophila melanogaster oviposition decisions PLoS One, 20(3):e0320377 PubMed ID: 40138267
Summary: Decisions where an individual lays their eggs are important, as the choice may affect their offspring's survival and lifetime reproductive success. Information produced by conspecifics can potentially be useful in making decisions as this "social information" may provide an energetically cheaper means of assessing oviposition site suitability rather than acquiring it personally. However, as not all public information may be equally beneficial, cues produced by kin may be especially valuable as they might signal suitable microenvironments, and are associated with other fitness advantages resulting from improved foraging success and/or a decreased risk of competition/cannibalism compared to sites where unrelated conspecifics are located. Using the fruit fly, Drosophila melanogaster, this study explored whether public information use is associated with kin-based egg-laying decisions. Kinship is potentially recognized in several ways, including environmentally-associated proxy cues, so this study explored whether there were biases in how focal females interacted with cues from conspecifics that differed in both genetic relatedness, and environmental "familiarity." In a series of inter-connected assays, the behaviour was examined of focal females that interacted with a choice of potential egg-laying substrates that differed in the manner of their prior conspecific exposure, and the offspring that eclosed from these different substrates were coundted. Sites that had exhibited cues produced by conspecific demonstrators were visited more, and yielded more focal offspring compared to unexposed substrates. Furthermore, patterns of bias in offspring production were consistent with ovipositing females exhibiting sensitivity to the kinship status of the prior substrate's occupants. The basis of the kinship categorization by ovipositing females appears to be based on phenotypes that reflect true genetic relatedness, but the nature of the social information can be affected by other factors. These results further highlight the potential usefulness of D. melanogaster as a model to understand the evolution of social behaviour in the expression of decision-making. | Liao, M., Liu, Y., Xu, Z., Fang, M., Yu, Z., Cui, Y., Sun, Z., Huo, R., Yang, J., Huang, F., Liu, M., Zhou, Q., Song, X., Han, H., Chen, S., Xu, X., Qin, X., He, Q., Ju, D., Wang, T., Thakkar, N., Hardin, P. E., Golden, S. S., Zhang, E. E. (2025). The P-loop NTPase RUVBL2 is a conserved clock component across eukaryotes Nature, 642(8066):165-173 PubMed ID: 40140583
Summary: The eukaryotic circadian clock keeps time by using a transcription-translation feedback loop, which exhibits an architecture that is conserved across a diverse range of organisms, including fungi, plants and animals. Despite their mechanistic similarity, the molecular components of these clocks indicate a lack of common ancestry. This study reveals that RUVBL2, which is a P-loop NTPase enzyme previously shown to affect circadian phase and amplitude as part of mammalian clock super-complexes, influences the circadian period through its remarkably slow ATPase activity, resembling the well-characterized KaiC-based clock in cyanobacteria. A screen of RUVBL2 variants identified arrhythmic, short-period and long-period mutants that altered circadian locomotor activity rhythms following delivery by adeno-associated virus to the murine suprachiasmatic nucleus. Enzymatic assays showed that wild-type RUVBL2 hydrolyses only around 13 ATP molecules a day, a vastly reduced turnover compared with typical ATPases. Notably, physical interactions between RUVBL2 orthologues (Reptin in Drosophila) and core clock proteins in humans, Drosophila and the fungus Neurospora, along with consistent circadian phenotypes of RUVBL2-mutant orthologues across species, reinforce their clock-related function in eukaryotes. Thus, as well as establishing RUVBL2 as a common core component in eukaryotic clocks, this study supports the idea that slow ATPase activity, initially discovered in cyanobacteria, is a shared feature of eukaryotic clocks. |
| Varone, M., Di Lillo, P., Nikolouli, K., ozel, A. E., Lucibelli, F., Volpe, G., Mazzucchiello, S. M., Carfora, A., Aceto, S., Saccone, G., Bourtzis, K., Salvemini, M. (2025). The Early Sex-Specific Expression of the Fruitless Gene in the Asian Tiger Mosquito Aedes albopictus (Skuse) and Its Functional Conservation in Male Courtship Insects, 16(3) PubMed ID: 40266775
Summary: The Asian tiger mosquito, Aedes albopictus, is an invasive species and a vector for several significant human pathogens. Gaining a deeper understanding of its reproductive biology offers valuable insights into its evolutionary success and may inform the development of sustainable strategies to control its spread. This study presents a comprehensive structural and functional characterization of the fruitless gene in Ae. albopictus (Aalfru), a pivotal regulator of sexual behavior in insects. Through in silico analysis combined with molecular and functional genetics approaches, we identified a high degree of conservation in the fru gene structure and its regulation via sex-specific alternative splicing. Differently from Drosophila, Aedes aegypti, and other dipteran fruitless orthologs, Aalfru sex-specific regulation starts in 1-day-old embryos, rather than the late larval stage. Functional analysis using embryonic RNA interference (RNAi) demonstrated that, Ae. albopictus males with transiently disrupted fru expression at the embryonic stage showed significant deficits in adult mating behavior and failed to produce viable progeny. Our findings elucidate the Aalfru gene's molecular organization, developmental regulation, and critical role in courtship behavior, highlighting its importance in male sexual behavior and reproductive success in Ae. albopictus. | Warecki, B., Vega, G., Fowler, S., Hartzog, G., Karr, T. L., Sullivan, W. (2025). Wolbachia-mediated reduction in the glutamate receptor mGluR promotes female promiscuity and bacterial spread Cell Rep, 44(5):115629 PubMed ID: 40347951
Summary: The molecular mechanisms by which parasites mediate host behavioral changes remain largely unexplored. This stusy examined Drosophila melanogaster infected with Wolbachia, a symbiont transmitted through the maternal germline, and found Wolbachia infection increases female receptivity to male courtship and hybrid mating. Wolbachia colonize regions of the brain that control sense perception and behavior. Quantitative global proteomics identify 177 differentially abundant proteins in infected female larval brains. Genetic alteration of the levels of three of these proteins in adults, the metabotropic glutamate receptor mGluR, the transcription factor AP-2, and the odorant binding protein bp99b, each mimic the effect of Wolbachia on female receptivity. Furthermore, >:700 Wolbachia proteins are detected in infected brains. Through abundance and molecular modeling analyses, we distinguish several Wolbachia-produced proteins were distinguish as potential effectors. These results identify potential networks of host and Wolbachia proteins that modify behavior to promote mating success and aid the spread of Wolbachia. |
| Liang, Y., Jiang, K., Liu, Z., Tu, J., Gong, W., Hu, Y., Li, J., Hardiman, G., Guo, X., Zhu, B. (2025). The role of molecular weight on chitosan and chitosan oligosaccharides in sleep regulation: Integrating network pharmacology and multi-omics analysis in Drosophila Int J Biol Macromol, 308(Pt 3):142147 PubMed ID: 40101831
Summary: This study aims to investigate the sleep-regulating effects of chitosan (COS) with different molecular weights (1 kDa, 3 kDa and 30 kDa). Network pharmacology predicted the sleep-regulating effects of COS and COS oligosaccharides and identified sleep-related targets. Drosophila sleep analysis demonstrated that COS ameliorated caffeine-induced insomnia, and its efficacy was critically influenced by molecular weight. Specifically, COS30K exhibited superior effects compared to COS1K and COS3K in improving the nighttime sleep time, duration of sleep episode and number of sleep episodes in flies. These differential effects were primarily related to acetate-producing bacteria Acetobacter and polysaccharide-degrading bacteria (Bacteroides and Ruminococcus). Their influence on tryptophan metabolism (serotonin and kynurenine) may contribute to the molecular weight-dependent differences in sleep-regulating effects of COS. Integration of network pharmacology and transcriptomic analyses identified five crucial targets (Insc, Aox1, bgm, Acer and hll). This study provides a strategy for predicting novel biological activity of COS and COS oligosaccharides. | Huang, S., Piao, C., Zhao, Z., Beuschel, C. B., Turrel, O., Toppe, D., Sigrist, S. J. (2025). Enhanced memory despite severe sleep loss in Drosophila insomniac mutants PLoS Biol, 23(3):e3003076 PubMed ID: 40111981
Summary: Sleep is crucial for cognitive functions and life span across species. While sleep homeostasis and cognitive processes are linked through cellular and synaptic plasticity, the signaling pathways connecting them remain unclear. This study shows that Drosophila insomniac (inc) short sleep mutants, which lack an adaptor protein for the autism-associated Cullin-3 ubiquitin ligase, exhibited enhanced Pavlovian aversive olfactory learning and memory, unlike other sleep mutants with normal or reduced memory. Through a genetic modifier screen, we found that a mild reduction of Protein Kinase A (PKA) signaling specifically rescued the sleep and longevity phenotypes of inc mutants. However, this reduction further increased their excessive memory and mushroom body overgrowth. Since inc mutants displayed higher PKA signaling, we propose that inc loss-of-function suppresses sleep via increased PKA activity, which also constrains the excessive memory of inc mutants. Our data identify a signaling cascade for balancing sleep and memory functions, and provide a plausible explanation for the sleep phenotypes of inc mutants, suggesting that memory hyperfunction can provoke sleep deficits. |
Friday April 10th - Disease Models |
| Mora, N., Slot, E. F. J., Lewandowski, V., Menafra, M. P., Mallik, M., van Lith, P., Sijlmans, C., van Bakel, N., Ignatova, Z., Storkebaum, E. (2025). Glycyl-tRNA sequestration is a unifying mechanism underlying GARS1-associated peripheral neuropathy. Nucleic Acids Res, 53(6) PubMed ID: 40119731
Summary: Dominantly inherited mutations in eight cytosolic aminoacyl-tRNA synthetase genes cause hereditary motor and sensory neuropathy, characterized by degeneration of peripheral motor and sensory axons. Previous work identified a pathogenic gain-of-toxic function mechanism underlying peripheral neuropathy (PN) caused by heterozygous mutations in the Glycyl-tRNA Synthetase 1 (GARS1) gene, encoding glycyl-tRNA synthetase (GlyRS). Specifically, PN-mutant GlyRS variants sequester tRNAGly, which depletes the cellular tRNAGly pool, leading to insufficient glycyl-tRNAGly available to the ribosome and consequently ribosome stalling at glycine codons. Given that GlyRS functions as a homodimer, a subset of PN-GlyRS mutations might alternatively cause peripheral neuropathy through a dominant negative loss-of-function mechanism. To explore this possibility, three novel PN-GlyRS Drosophila models expressing human PN-GlyRS (hGlyRS) variants that do not alter the overall GlyRS protein charge (S211F and H418R) where generated, and a single reported PN-GlyRS variant that renders the GlyRS protein charge more negative (K456Q) was also generated. High-level expression of hGlyRS-K456Q did not induce peripheral neuropathy and the K456Q variant does not affect aminoacylation activity, suggesting that K456Q is not a pathogenic mutation. Expression of hGlyRS-S211F or hGlyRS-H418R in Drosophila did induce peripheral neuropathy and de novo protein synthesis defects. Genetic and biochemical evidence indicates that these phenotypes were attributable to tRNAGly sequestration rather than a dominant negative mechanism. These data identify tRNAGly sequestration as a unifying pathogenic mechanism underlying PN-GlyRS. | Neuman, S. D., Thakur, R. S., Gratz, S. J., O'Connor-Giles, K. M., Bashirullah, A. (2025). Neurodegenerative and Neurodevelopmental Roles for Bulk Lipid Transporters VPS13A and BLTP2. Mov Disord, PubMed ID: 40152532
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. The objective of this study was to determine tissue-specific and aging-dependent roles for VPS13A and BLTP2 using Drosophila models. METHODS: Tissue-specific knockdowns were generated of the VPS13A ortholog (Vps13) and the BLTP2 ortholog (hobbit) in neurons and muscles of Drosophila. Age-dependent locomotor behavior, neurodegeneration, and synapse development and function were analyzed. Neuron-specific loss of the VPS13A ortholog caused neurodegeneration followed by aging-dependent movement deficits and reduced lifespan, whereas muscle-specific loss affected only lifespan. In contrast, neuronal loss of the BLTP2 ortholog resulted in severe early-onset locomotor defects without neurodegeneration, whereas muscle loss impaired synaptogenesis and neurotransmission at the neuromuscular junction. It is concluded that VPS13A maintains neuronal survival, whereas BLTP2 orchestrates synaptic development. The phenotypic specificity of BLTP function provides mechanistic insights into distinct disease trajectories for BLTP-associated disorders. |
| Nagori, R., Vigoreaux, J. O. (2025). beta-hydroxy-beta-methylbutyrate Attenuates Age-Dependent Loss of Flight Ability and Extends Lifespan in Drosophila Int J Mol Sci, 26(6) PubMed ID: 40141306
Summary: β-hydroxy-β-methylbutyrate (HMB) has been shown to enhance muscle function and strength in older humans and rodents after periods of consumption extending for several weeks. This study investigated the feasibility of utilizing Drosophila as a model organism to study the biological effects of HMB on aging muscle when consumed throughout adult life. Using flight ability as an index of flight muscle function, HMB was found to attenuate the age-dependent decline in flight ability. Male and female flies fed a diet supplemented with 10 mg/mL HMB had significantly higher flight scores from median age until the onset of flight senescence than control flies fed a standard diet. HMB supplementation also resulted in improved flight scores in males before median age and delayed the onset of flight senescence in females. Notably, the consumption of HMB throughout adult life increased the rate of survival and extended lifespan. The effect on lifespan did not result from changes in food consumption or body weight. Old flies on the HMB-supplemented diet retained a higher proportion of flight muscle mitochondria whose morphology resembled that of young flies than the control diet group. Together, these results suggest that HMB attenuates the age-dependent decline in flight ability and prolongs lifespan by enhancing muscle health. | Moore, J., Wu, T., Dhindsa, J., El Fadel, O., Le, A., Perez, A., Amoh, B., Tarkunde, A., Zhu, K. F., Avalos, M., Dammer, E. B., Duong, D. M., Seyfried, N. T., Shulman, J. M., Al-Ramahi, I., Botas, J. (2025). Longitudinal multi-omics in alpha-synuclein Drosophila model discriminates disease- from age-associated pathologies in Parkinson's disease. NPJ Parkinsons Dis, 11(1):46 PubMed ID: 40069190
Summary: Parkinson's disease (PD) starts decades before symptoms appear, usually in the later decades of life, when age-related changes are occurring. To identify molecular changes early in the disease course and distinguish PD pathologies from aging, Drosophila were generated expressing alpha-synuclein (αSyn) in neurons, and longitudinal bulk transcriptomics and proteomics were performed on brains at six time points across the lifespan and compared the data to healthy control flies as well as human post-mortem brain datasets. Translational and energy metabolism pathways were downregulated in αSyn flies at the earliest timepoints; comparison with the aged control flies suggests that elevated αSyn accelerates changes associated with normal aging. Unexpectedly, single-cell analysis at a mid-disease stage revealed that neurons upregulate protein synthesis and nonsense-mediated decay, while glia drive their overall downregulation. Longitudinal multi-omics approaches in animal models can thus help elucidate the molecular cascades underlying neurodegeneration vs. aging and co-pathologies. |
| Stefanatos, R., Robertson, F., Castejon-Vega, B., Yu, Y., Uribe, A. H., Myers, K., Kataura, T., Korolchuk, V. I., Maddocks, O. D. K., Martins, L. M., Sanz, A. (2025). Developmental mitochondrial complex I activity determines lifespan EMBO Rep, 26(8):1957-1983 PubMed ID: 40097814
Summary: Aberrant mitochondrial function has been associated with an increasingly large number of human disease states. Observations from in vivo models where mitochondrial function is altered suggest that maladaptations to mitochondrial dysfunction may underpin disease pathology. It was hypothesized that the severity of this maladaptation could be shaped by the plasticity of the system when mitochondrial dysfunction manifests. To investigate this, inducible fly models of mitochondrial complex I (CI) dysfunction were used to reduce mitochondrial function at two stages of the fly lifecycle, from early development and adult eclosion. This study showed that in early life (developmental) mitochondrial dysfunction results in severe reductions in survival and stress resistance in adulthood, while flies where mitochondrial function is perturbed from adulthood, are long-lived and stress resistant despite having up to a 75% reduction in CI activity. After excluding developmental defects as a cause, these two populations of mitochondrially compromised flies, short- and long-lived, were molecularly characterized. The short-lived flies have unique transcriptomic, proteomic and metabolomic responses, which overlap significantly in discrete models of CI dysfunction. | Poudel, S., Chuang, C. L., Shrestha, H. K., Demontis, F. (2025). Pan-PTM profiling identifies post-translational modifications associated with exceptional longevity and preservation of skeletal muscle function in Drosophila NPJ Aging, 11(1):23 PubMed ID: 40159514
Summary: Skeletal muscle weakness is a major component of age-associated frailty, but the underlying mechanisms are not completely understood. Drosophila has emerged as a useful model for studying skeletal muscle aging. In this organism, previous lab-based selection established strains with increased longevity and reduced age-associated muscle functional decline compared to a parental strain. This study has applied a computational pipeline (JUMPptm) for retrieving information on 8 post-translational modifications (PTMs) from the skeletal muscle proteomes of 2 long-lived strains and the corresponding parental strain in young and old age. This pan-PTM analysis identified 2470 modified sites (acetylation, carboxylation, deamidation, dihydroxylation, mono-methylation, oxidation, phosphorylation, and ubiquitination) in several classes of proteins, including evolutionarily conserved muscle contractile proteins and metabolic enzymes. PTM consensus sequences further highlight the amino acids that are enriched adjacent to the modified site, thus providing insight into the flanking residues that influence distinct PTMs. Altogether, these analyses identify PTMs associated with muscle functional decline during aging and that may underlie the longevity and negligible functional senescence of lab-evolved Drosophila strains. |
Thursday April 9th - Neural Development in the embryo |
| Pollington, H. Q., Doe, C. Q. (2025). The Hunchback transcription factor determines interneuron molecular identity, morphology, and presynapse targeting in the Drosophila NB5-2 lineage PLoS Biol, 23(3):e3002881 PubMed ID: 40163536
Summary: Interneuron diversity with (CNS) is essential for proper circuit assembly. Functional interneurons must integrate multiple features, including combinatorial transcription factor (TF) expression, axon/dendrite morphology, and connectivity to properly specify interneuronal identity. Yet, how these different interneuron properties are coordinately regulated remains unclear. Fhis study used the Drosophila neural progenitor, NB5-2, known to generate late-born interneurons in a proprioceptive circuit, to determine if the early-born temporal transcription factor (TTF), Hunchback (Hb), specifies early-born interneuron identity, including molecular profile, axon/dendrite morphology, presynapse targeting, and behavior. Prolonged Hb expression in NB5-2 increases the number of neurons expressing early-born TFs (Nervy, Nkx6, and Dbx) at the expense of late-born TFs (Runt and Zfh2); thus, Hb is sufficient to promote interneuron molecular identity. Hb is also sufficient to transform late-born neuronal morphology to early-born neuronal morphology. Furthermore, prolonged Hb promotes the relocation of late-born neuronal presynapses to early-born neuronal presynapse neuropil locations, consistent with a change in interneuron connectivity. Finally, this study found that prolonged Hb expression led to defects in proprioceptive behavior, consistent with a failure to properly specify late-born interneurons in the proprioceptive circuit. It is concluded that the Hb TTF is sufficient to specify multiple aspects of early-born interneuron identity, as well as disrupt late-born proprioceptive neuron function. | Ramya, R., Venkatesh, C. R., Shyamala, B. V. (2024). olf413 an octopamine biogenesis pathway gene is required for axon growth and pathfinding during embryonic nervous system development in Drosophila melanogaster BMC Res Notes, 17(1):46 PubMed ID: 38326892
Summary: Neurotransmitters have been extensively studied as neural communication molecules. Genetic associations discovered, and indirect intervention studies in Humans and mammals have led to a general proposition that neurotransmitters have a role in structuring of neuronal network during development. olf413 is a Drosophila gene annotated as coding for dopamine β-monooxygenase enzyme with a predicted function in octopaminergic pathway. The biological function of this gene is very little worked out. This study investigated the requirement of olf413 gene function for octopamine biogenesis and developmental patterning of embryonic nervous system. This study used the newly characterized neuronal specific allele olf413SG1.1), and the gene disruption strain olf413MI02014) to dissect out the function of olf413. olf413 has an enhancer activity as depicted by reporter GFP expression, in the embryonic ventral nerve cord, peripheral nervous system and the somatic muscle bundles. Homozygous loss of function mutants show reduced levels of octopamine, and this finding supports the proposed function of the gene in octopamine biogenesis. Further, loss of function of olf413 causes embryonic lethality. FasII staining of these embryos reveal a range of phenotypes in the central and peripheral motor nerves, featuring axonal growth, pathfinding, branching and misrouting defects. These findings are important as they implicate a key functional requirement of this gene in precise axonal patterning events, a novel developmental role imparted for an octopamine biosynthesis pathway gene in structuring of embryonic nervous system. |
| Hunter, I., Coulson, B., Pettini, T., Davies, J. J., Parkin, J., Landgraf, M., Baines, R. A. (2024). Balance of activity during a critical period tunes a developing network Elife, 12 PubMed ID: 38193543
Summary: Developing neural circuits are influenced by activity and are especially sensitive to changes in activity during critical periods (CPs) of development. Changes occurring during a CP often become 'locked in' so that they affect the mature network. Indeed, several neurodevelopmental disorders have been linked to excessive activity during such periods. It is, therefore, important to identify those aspects of neural circuit development that are influenced by neural activity during a CP. In this study, advantage was taken of the genetic tractability of Drosophila to show that activity perturbation during an embryonic CP permanently alters properties of the locomotor circuit. Specific changes identified include increased synchronicity of motoneuron activity and greater strengthening of excitatory over inhibitory synaptic drive to motoneurons. These changes are sufficient to reduce network robustness, evidenced by increased sensitivity to induced seizure. It was also shown that it is possible to rescue these changes when increased activity is mitigated by inhibition provided by mechanosensory neurons. Similarly, a dose-dependent relationship was demonstrated between inhibition experienced during the CP and the extent to which it is possible to rescue the hyperexcitable phenotype characteristic of the parabss mutation. This suggests that developing circuits must be exposed to a properly balanced sum of excitation and inhibition during the CP to achieve normal mature network function. These results, therefore, provide novel insight into how activity during a CP shapes specific elements of a circuit, and how activity during this period is integrated to tune neural circuits to the environment in which they will likely function. | Bui, K. C., Kamiyama, D. (2024). Adjacent Neuronal Fascicle Guides Motoneuron 24 Dendritic Branching and Axonal Routing Decisions through Dscam1 Signaling bioRxiv, PubMed ID: 38645010
Summary: The formation and precise positioning of axons and dendrites are crucial for the development of neural circuits. Although juxtracrine signaling via cell-cell contact is known to influence these processes, the specific structures and mechanisms regulating neuronal process positioning within the central nervous system (CNS) remain to be fully identified. This study investigates motoneuron 24 (MN24) in the Drosophila embryonic CNS, which is characterized by a complex yet stereotyped axon projection pattern, known as 'axonal routing.' In this motoneuron, the primary dendritic branches project laterally toward the midline, specifically emerging at the sites where axons turn. Scp2 positive neurons contribute to the lateral fascicle structure in the ventral nerve cord (VNC)Down syndrome cell adhesion molecule (dscam1) results in the loss of dendrites and disruption of proper axonal routing in MN24, while not affecting the formation of the fascicle structure. Through cell-type specific knockdown and rescue experiments of dscam1, This study has determined that the interaction between MN24 and Scp2-positive fascicle, mediated by Dscam1, promotes the development of both dendrites and axonal routin. These findings demonstrate that the holistic configuration of neuronal structures, such as axons and dendrites, within single motoneurons can be governed by local contact with the adjacent neuron fascicle, a novel reference structure for neural circuitry wiring. |
| McLamb, F., Feng, Z., Vu, J. P., Griffin, L., Vasquez, M. F., Bozinovic, G. (2024). Lagging Brain Gene Expression Patterns of Drosophila melanogaster Young Adult Males Confound Comparisons Between Sexes. Molecular neurobiology, PubMed ID: 39196495
Summary: Many species, including fruit flies (Drosophila melanogaster), are sexually dimorphic. Phenotypic variation in morphology, physiology, and behavior can affect development, reproduction, health, and aging. Therefore, designating sex as a variable and sex-blocking should be considered when designing experiments. The brain regulates phenotypes throughout the lifespan by balancing survival and reproduction, and sex-specific development at each life stage is likely. Changes in morphology and physiology are governed by differential gene expression, a quantifiable molecular marker for age- and sex-specific variations. This study assessed the fruit fly brain transcriptome at three adult ages for gene expression signatures of sex, age, and sex-by-age: 6698 genes were differentially expressed between sexes, with the most divergence at 3 days. Between ages, 31.1% of 6084 differentially expressed genes (1890 genes) share similar expression patterns from 3 to 7 days in females, and from 7 to 14 days in males. Most of these genes (90.5%, 1712) were upregulated and enriched for chemical stimulus detection and/or cilium regulation. These data highlight an important delay in male brain gene regulation compared to females. Because significant delays in expression could confound comparisons between sexes, studies of sexual dimorphism at phenotypically comparable life stages rather than chronological age should be more biologically relevant. | Lefebvre, M., Colen, J., Claussen, N., Brauns, F., Raich, M., Mitchell, N., Fruchart, M., Vitelli, V., Streichan, S. J. (2024). Learning a conserved mechanism for early neuroectoderm morphogenesis ArXiv, PubMed ID: 38855544
Summary: Morphogenesis is the process whereby the body of an organism develops its target shape. The morphogen BMP is known to play a conserved role across bilaterian organisms in determining the dorsoventral (DV) axis. Yet, how BMP governs the spatio-temporal dynamics of cytoskeletal proteins driving morphogenetic flow remains an open question. This study used machine learning to mine a morphodynamic atlas of Drosophila development, and construct a mathematical model capable of predicting the coupled dynamics of myosin, E-cadherin, and morphogenetic flow. Mutant analysis shows that BMP sets the initial condition of this dynamical system according to the following signaling cascade: BMP establishes DV pair-rule-gene patterns that set-up an E-cadherin gradient which in turn creates a myosin gradient in the opposite direction through mechanochemical feedbacks. Using neural tube organoids, this study argues that BMP, and the signaling cascade it triggers, prime the conserved dynamics of neuroectoderm morphogenesis from fly to humans. |
Wednesday April 8th - Growth and Cancer |
| Padash Barmchi, M., Hassan, R. N., Afkhami, M., Masly, J. P., Brown, H., Collins, Q. P., Grunsted, M. J. (2025). Drosophila model of HPV18-Induced pathogenesis reveals a role for E6 oncogene in regulation of NF-kaooaB and Wnt to inhibit apoptosis Tumour Virus Res, 19:200316 PubMed ID: 40074036
Summary: Cancers caused by high-risk human papillomavirus (HPV) remain a significant health threat resulting in more than 300,000 deaths, annually. Persistent expression of two HPV oncogenes, E6 and E7, are necessary for cancer development and progression. E6 has several functions contributing to tumorigenesis one of which is blocking programmed cell death, apoptosis. The detailed mechanism of anti-apoptosis function of E6 is not fully understood. Using a Drosophila model of HPV18E6 and the human UBE3A-induced pathogenesis, this study showed that anti-apoptotic function of E6 is conserved in Drosophila. The Drosophila homologs of human NF-kappaB transcription factors, Dorsal and Dif are proapoptotic. They induce the expression of Wingless (Wg, the Drosophila homolog of human Wnt), leading to apoptosis. The results indicate that E6 oncogene inhibits apoptosis by downregulating the expression of Wg, Dorsal, and Dif. Additionally, this study found that Dorsal and Dif, not only promote apoptosis but also regulate autophagy and necrosis. Dorsal promotes autophagy while Dif counteracts it, inducing the formation of acidic vacuoles and necrosis. Interestingly, although E6 blocks the proapoptotic function of Dorsal and Dif, it lacks the ability to interfere with their role in apoptosis-independent cell death. Given the high conservation of NF-kappaB transcription factors our results provide new insight into potential mechanisms mediated by NF-kappaB to intervene with cell immortalization action of E6 oncoprotein in HPV-infected cells. | Molano-Fernandez, M., Hickson, I. D., Herranz, H. (2025). Replication stress promotes cellular transformation in Drosophila epithelium Cell Death Discov, 11(1):96 PubMed ID: 40075075
Summary: The accurate control of DNA replication is crucial for the maintenance of genomic stability and cell viability. This study explored the consequences of depleting the replicative DNA Polymerase α (POLA) in the wing disc of Drosophila melanogaster. The findings of this study reveal that reduced POLA activity induces DNA replication stress and activates the replication checkpoint in vivo. Consistent with this, it was demonstrated that dATR, a key component in DNA replication checkpoint signaling, is essential for the maintenance of tissue integrity under conditions of compromised POLA activity. Cells within the wing disc exhibiting reduced POLA activity arrest in the G2 phase and undergo p53-dependent apoptosis. This study also reveal a critical role for DNA Ligase 4 in sustaining cell viability when POLA function is impaired. Most notably, this study reports the appearance of oncogenic traits in wing disc cells with diminished POLA activity when apoptosis is suppressed. In this context, the overexpression of the oncogene cdc25/string enhances the oncogenic phenotype. These results indicate that a combination of oncogenic activation, replication stress, and suppression of apoptosis is sufficient to promote the emergence of hallmarks of tumorigenesis, highlighting major implications for cancer development in humans. |
| Hirata, M., Nomura, T., Inoue, Y. H. (2025). Anti-Tumor Effects of Cecropin A and Drosocin Incorporated into Macrophage-like Cells Against Hematopoietic Tumors in Drosophila mxc Mutants Cells, 14(6) PubMed ID: 40136638
Summary: Five major antimicrobial peptides (AMPs) in Drosophila are induced in multiple sex combs (mxc) mutant larvae harboring lymph gland (LG) tumors, and they exhibit anti-tumor effects. The effects of other well-known AMPs, Cecropin A and Drosocin, remain unexplored. This study investigated the tumor-elimination mechanism of these AMPs. A half-dose reduction in either the Toll or Imd gene reduced the induction of these AMPs and enhanced tumor growth in mxcmbn1 mutant larvae, indicating that their anti-tumor effects depend on the innate immune pathway. Overexpression of these AMPs in the fat body suppressed tumor growth without affecting cell proliferation. Apoptosis was promoted in the mutant but not in normal LGs. Conversely, knockdown of these genes inhibited apoptosis and enhanced tumor growth; therefore, they inhibit LG tumor growth by inducing apoptosis. The AMPs from the fat body were incorporated into the hemocytes of mutant but not normal larvae. Another AMP, Drosomycin, was taken up via phagocytosis factors. Enhanced phosphatidylserine signals were observed on the tumor surface. Inhibition of the signals exposed on the cell surface enhanced tumor growth. AMPs may target phosphatidylserine in tumors to induce apoptosis and execute their tumor-specific effects. AMPs could be beneficial anti-cancer drugs with minimal side effects for clinical development. | Tsai, M., Sun, J., Alexandre, C., Shapiro, M., Franchet, A., Li, Y., Gould, A. P., Vincent, J. P., Stockinger, B., Diny, N. L. (2025). Drosophila AHR limits tumor growth and stem cell proliferation in the intestine Wellcome Open Res, 10:38 PubMed ID: 40212817
Summary: The aryl hydrocarbon receptor (AHR) plays important roles in intestinal homeostasis, limiting tumour growth and promoting differentiation in the intestinal epithelium. Spineless, the Drosophila homolog of AHR, has only been studied in the context of development but not in the adult intestine. The role of Spineless in the Drosophila was studied by overexpression or inactivation of Spineless in infection and tumour models and RNA sequencing of sorted midgut progenitor cells. Spineless is upregulated in the adult intestinal epithelium after infection with Pseudomonas entomophila ( P. e.). Spineless inactivation increased stem cell proliferation following infection-induced injury. Spineless overexpression limited intestinal stem cell proliferation and reduced survival after infection. In two tumour models, using either Notch RNAi or constitutively active Yorkie, Spineless suppressed tumour growth and doubled the lifespan of tumour-bearing flies. At the transcriptional level it reversed the gene expression changes induced in Yorkie tumours, counteracting cell proliferation and altered metabolism. These findings demonstrate a new role for Spineless in the adult Drosophila midgut and highlight the evolutionarily conserved functions of AHR/Spineless in the control of proliferation and differentiation of the intestinal epithelium. |
| Bellec, K., Carroll, L. R., Pennel, K. A. F., Tian, Y., Yu, Y., Akan, A. B., Billard, C. V., Doleschall, N., Cameron, A. R., Heredia, F., Gontijo, A. M., Ochocka-Fox, A. M., Blackmur, J. P., Din, F. V. N., Dunlop, M. G., Edwards, J., Myant, K., Hayashi, R., Cordero, J. B. (2026). Non-gonadal PIWIL1/Aubergine drives regenerative and tumorigenic stem cell proliferation and tumorigenesis in the intestine Cell Rep, 45(4):117186 PubMed ID: 41894395
Summary: The PIWI-interacting RNA (piRNA) biosynthesis pathway is best studied for its role in suppressing Drosophila germline transposable elements. Piwi, the founding member of the pathway, is involved in adult intestinal stem cell (ISC) homeostasis. Whether a broader role of the PIWI pathway exists in the intestine remains unknown. This study characterizes a role of the PIWI family protein Aubergine (Aub) in ISCs. While dispensable for basal ISC self-renewal, upregulation of Aub by damage-induced reactive oxygen species drives regenerative ISC proliferation through increased protein synthesis, including translation of ISC factors Myc and Sox21a. Unexpectedly, such roles of Aub in ISCs appear uncoupled from its piRNA regulatory function. Additionally, Aub and mammalian PIWIL1 mediate tumorigenic intestinal growth in Drosophila and human organoids, respectively. These results reveal regulated protein translation as a fundamental aspect of regenerative ISC function and discover a central role of Aub in such process. | Zhu, Y., Wunderlich, Z., Lander, A. D. (2025). Epithelial cell competition is promoted by signaling from immune cells Nat Commun, 16(1):3710 PubMed ID: 40251197
Summary: In epithelial tissues, juxtaposition of cells of different phenotypes can trigger cell competition, a process whereby one type of cell drives death and extrusion of another. During growth and homeostasis, cell competition is thought to serve a quality control function, eliminating cells that are "less fit". Tissues may also attack and eliminate newly arising tumor cells, exploiting mechanisms shared with other instances of cell competition, but that differ, reportedly, in the involvement of the immune system. Whereas immune cells have been shown to play a direct role in killing tumor cells, this has not been observed in other cases of cell competition, suggesting that tissues recognize and handle cancer cells differently. This study challenges this view, showing that, in the fruit fly Drosophila, innate immune cells play similar roles in cell killing during classical cell competition as in eliminating tumors. These findings suggest that immune suppression of cancer may exploit the same mechanisms as are involved in promoting phenotypic uniformity among epithelial cells. |
Tuesday April 7th - Gonads |
| Kotb, N. M., Ulukaya, G., Ramamoorthy, A., Park, L. S., Tang, J., Hasson, D., Rangan, P. (2025). TORC1-driven translation of Nucleoporin44A promotes chromatin remodeling and germ cell-to-maternal transition in Drosophila bioRxiv, PubMed ID: 40161787Summary: Oocyte specification is a critical developmental transition that requires the coordinated repression of germ cell-specific genes and activation of the maternal program to support embryogenesis. In Drosophila, the timely repression of germ cell and early oogenesis genes is essential for this transition, yet the mechanisms that coordinate this process remain unclear. This study uncovered an unexpected translation-chromatin axis, where transient Target of Rapamycin Complex 1 (TORC1)-driven translation triggers chromatin remodeling, ensuring irreversible oocyte fate commitment. Through a screen, ribosome biogenesis regulators, including Zinc finger protein RP-8 (Zfrp8) and TORC1 components, were identified as key mediators of gene silencing. TORC1 activity increases during oocyte specification, and disrupting ribosome biogenesis, translation, or TORC1 function prevents proper heterochromatin formation, leading to epigenetic instability. Polysome-seq analysis of zfrp-depleted ovaries revealed that Zfrp8 is required for the translation of Nucleoporin 44A (Nup44A), a key nuclear pore complex (NPC) component. Given the role of the NPC in chromatin organization, independent disruption of Nup44A results in defective silencing of the germ cell and early oogenesis genes. These findings reveal a mechanism in which translation-driven NPC remodeling coordinates heterochromatin establishment, facilitating the germ cell-to-maternal transition and ensuring proper oocyte fate commitment. | Elshaer, N., Escudero, J., Piulachs, M. D. (2025). The transcription factor Capicua maintains the oocyte polarity in the panoistic ovary of the German cockroach Dev Biol, 522:125-135 PubMed ID: 40158791
Summary: The establishment of the symmetry axis is crucial for the development of all organisms. In insects, this process begins early in oogenesis with the correct distribution of the mRNAs and proteins in the oocyte. One protein that plays a role in organizing this distribution is the transcription factor Capicua (Cic). Cic has been studied in the context of oogenesis and embryonic development in Drosophila melanogaster. It is maternally expressed, begins essential for establishing the dorsoventral axis, and functions as a transcriptional repressor. Although the Cic sequences are conserved across species, their function in other types of insect ovaries is still little known. This study asked whether the function of Cic in insects has been maintained through evolution despite the ovary type or if it has been modified in parallel to the ovary evolution. To address this, the Cic function was studied in a phylogenetically basal insect, the cockroach Blattella germanica, a species with panoistic ovaries. The findings show that B. germanica Cic is essential for oocyte development and the maturation of ovarian follicles. A loss of Cic function leads to disrupted cytoskeletal organization, defects in anterior-posterior polarity, and compromised follicle integrity. The conservation and functional divergence of Cic across different species suggest evolutionary adaptations in the mechanisms of insect oogenesis. |
| Wang, Q., Chen, X., Wang, Y. F. (2025). Sec61beta, a subunit of the Sec61 complex at the endoplasmic reticulum, coordinates with Ocnus in regulating Drosophila spermatogenesis Insect Biochem Mol Biol, 180:104310 PubMed ID: 40194670
Summary: sec61β encodes a subunit of the Sec61 translocon which is a highly conserved heterotrimer responsible for translocating the nascent polypeptides into the lumen of the endoplasmic reticulum (ER) or onto the ER membrane. This study shows that knockdown of sec61β in the early germline leads to male sterility in Drosophila melanogaster. These males exhibit testes that are dramatically reduced in size and devoid of germ cells. However, the somatic cells with hub markers extend abnormally beyond the stem cell niche region. Stat92E-positive cells are also expanded into the posterior region of the small testes and primarily in the nuclei. Through tracking the developmental processes of germ cells, this study found that the loss of germ cells occurs during the 3rd instar larval stage. Additionally, studies in Drosophila S2 cells reveal that sec61βSec61β can directly interact with Ocnus (Ocn), likely at the nuclear membrane. Genetically, overexpression of ocn partially restores fertility in sec61β knockdown males, while overexpression of sec61β fails to compensate for the defects in male fertility induced by ocn knockdown. These findings suggest that Sec61β might play a critical role in testis development and spermatogenesis, potentially coordinating with Ocn and involving in the JAK/STAT pathway. | Oka, M., Nakajima, S., Suzuki, E., Yamamoto, S., Ando, K. (2025). Glucose uptake in pigment glia suppresses Tau-induced inflammation and photoreceptor degeneration Dis Model Mech, 18(4) PubMed ID: 40151148
Summary: Brain inflammation contributes to the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD). Glucose hypometabolism and glial activation are pathological features seen in AD brains; however, the connection between the two is not fully understood. Using a Drosophila model of AD, this study identified that glucose metabolism in glia plays a critical role in neuroinflammation under disease conditions. Expression of human MATP (hereafter referred to as Tau) in the retinal cells, including photoreceptor neurons and pigment glia, causes photoreceptor degeneration accompanied by the formation of dark-stained round inclusion-like structures and swelling of the lamina cortex. Inclusion-like structures are formed by glial phagocytosis, and swelling of the laminal cortex correlates with the expression of antimicrobial peptides. Coexpression of human glucose transporter 3 (SLC2A3, hereafter referred to as GLUT3) with Tau in the retina does not affect Tau levels but suppresses these inflammatory responses and photoreceptor degeneration. Expression of GLUT3, specifically in the pigment glia, is sufficient to suppress inflammatory phenotypes and mitigate photoreceptor degeneration in the Tau-expressing retina. These results suggest that glial glucose metabolism contributes to inflammatory responses and neurodegeneration in tauopathy. |
| Even-Ros, D., Huertas-Romero, J., Marin-Menguiano, M., Nusspaumer, G., Borge, M., Irimia, M., Zurita, F., Gonzalez-Reyes, A. (2025). Drosophila ovarian stem cell niche ageing involves coordinated changes in transcription and alternative splicing Nat Commun, 16(1):2596 PubMed ID: 40091053
Summary: Gene expression (GE) and alternative splicing (AS) contribute to the formation of new interaction networks with potentially significant cellular functions. This study investigated ageing in the Drosophila female germline stem cell (GSC) niche; functional changes in both GE and AS are described. The GSC niche comprises three types of support cells, whose ageing transcriptomes reveal differential GE and AS variations related to cell adhesion, cytoskeleton and neural signalling. Because each population show distinctive GE and AS changes, niche cell types possess unique ageing signatures. Depending on the cell population, groups of genes display changes in both GE and AS, revealing a coordinated regulation of transcription and splicing during niche ageing. One such gene is Fasciclin 2, a neural adhesion molecule that we find is essential for niche functioning. Furthermore, genes involved in AS undergo changes in GE and/or AS themselves, providing a mechanistic explanation for the coordination of these two processes during niche ageing. This is the case of the splicing factor Smu1, described here as a key element necessary for ovarian niche homeostasis. | Noh, S., Na, S., Song, X., Hyun, S. (2025). Germline expression of Imp-L2 in Drosophila females enhances reproductive activity and longevity Anim Cells Syst (Seoul), 29(1):31-40 PubMed ID: 40103616
Summary: The Imaginal morphogenesis protein-Late 2 (Imp-L2) in Drosophila is recognized as a functional homolog of the insulin-like growth factor (IGF) binding protein family. This study reports that Imp-L2 expression in germline cells during oogenesis simultaneously enhances both fecundity and lifespan in female Drosophila. Loss of Imp-L2, either through knockout or germline-specific knockdown, resulted in decreased reproductive activity, as evidenced by reduced ovary size and fecundity, along with a higher proportion of infertile flies. Conversely, overexpression of Imp-L2 specifically in germline cells enhanced reproductive activity. Imp-L2 appears to regulate germline stem cell proliferation and differentiation independently of IGF signaling. Interestingly, germline-specific knockdown of Imp-L2 shortened the lifespan of female flies, whereas its overexpression extended it. Thus, Imp-L2 expression in the germline promotes both reproductive activity and longevity, presenting an exception to the typical trade-off between reproduction and lifespan. |
Friday April 3rd - Cell Cycle |
| Leca, N., Barbosa, F., Rodriguez-Calado, S., Esposito Verza, A., Moura, M., Pedroso, P. D., Pinto, I., Artes, E., Bange, T., Sunkel, C. E., Barisic, M., Maresca, T. J., Conde, C. (2025). Proximity-based activation of AURORA A by MPS1 potentiates error correction Curr Biol, 35(8):1935-1947.e1938 PubMed ID: 40203828
Summary: Faithful cell division relies on mitotic chromosomes becoming bioriented with each pair of sister kinetochores bound to microtubules oriented toward opposing spindle poles. Erroneous kinetochore-microtubule attachments often form during early mitosis but are destabilized through the phosphorylation of outer kinetochore proteins by centromeric AURORA B kinase (ABK) and centrosomal AURORA A kinase (AAK), thus allowing for re-establishment of attachments until biorientation is achieved. MPS1-mediated phosphorylation of NDC80 has also been shown to directly weaken the kinetochore-microtubule interface in yeast. In human cells, MPS1 has been proposed to transiently accumulate at end-on attached kinetochores and phosphorylate SKA3 to promote microtubule release. Whether MPS1 directly targets NDC80 and/or promotes the activity of AURORA kinases in metazoans remains unclear. This study reports a novel mechanism involving communication between kinetochores and centrosomes, wherein MPS1 acts upstream of AAK to promote error correction. MPS1 on pole-proximal kinetochores phosphorylates the C-lobe of AAK, thereby increasing its activation at centrosomes. This proximity-based activation ensures the establishment of a robust AAK activity gradient that locally destabilizes mal-oriented kinetochores near spindle poles. Accordingly, MPS1 depletion from Drosophila cells causes severe chromosome misalignment and erroneous kinetochore-microtubule attachments, which can be rescued by tethering either MPS1 or constitutively active AAK mutants to centrosomes. Proximity-based activation of AAK by MPS1 also occurs in human cells to promote AAK-mediated phosphorylation of the NDC80 N-terminal tail. These findings uncover an MPS1-AAK crosstalk that is required for efficient error correction, showcasing the ability of kinetochores to modulate centrosome outputs to ensure proper chromosome segregation. | Goldstein, B., Sheikh-Suliman, S., Bakhrat, A., Abdu, U. (2025). The differential roles of rad9 alternatively spliced forms in double- strand DNA break repair during Drosophila meiosis DNA Repair (Amst), 149:103833 PubMed ID: 40250145
Summary: The 9-1-1 complex, comprising the Rad9, Hus1 and Rad1 proteins, is believed to operate as a component of a DNA damage checkpoint pathway. An initial analysis of the Drosophila hus1 gene showed that Hus1 plays a dual role in meiosis, regulating both meiotic DNA damage checkpoint and homologous recombination repair. This study further analyzed the meiotic roles of another protein in the complex, Rad9, which has two alternatively spliced forms, Rad9A and Rad9B. Using CRISPR/Cas9, this study generated flies mutant for both rad9 isoforms. Similarly to hus1, mutations in rad9 lead to female sterility. Also, double-strand DNA breaks (DSBs) that form during meiosis are not processed efficiently, and the DNA within the oocyte nucleus fails to form its characteristic shape in rad9 mutants. On the other hand, the hus1 mutation completely disrupts checkpoint activation in DSB repair enzyme mutants, whereas the rad9 mutation only partially impairs checkpoint activation in this context. Moreover, spatial rescue experiments revealed that Rad9B is efficient in repairing meiotic DSBs, while Rad9A is not. Furthermore, female fertility in rad9 mutants depends on early efficient meiotic DSB repair but not on karyosome formation. In summary, these results demonstrate a differential role of Rad9 alternatively spliced forms during Drosophila meiosis in oogenesis, and while former studies showed that Hus1 is sufficient for the effective activation of the meiotic recombination checkpoint, these results revealed that this is not true for Rad9. |
| Hylton, C. A., Hansen, K., Tomkiel Dean, J. E. (2025). Pairing between homologous sequences on the X and chromosome 3 in Drosophila male meiosis Genetics, 230(2) PubMed ID: 40147874
Summary: Pairing between sex chromosomes in male Drosophila normally occurs at intergenic spacer (IGS) sequences within the tandemly repeated rDNA genes that are located proximally in the heterochromatin on both the X and Y. Pairing is not limited to these sequences, however, and can also occur with high fidelity between the X and segments of X euchromatin that have been translocated to the Y. Such euchromatic pairings can lead to segregation of the X and Y, even when the X is rDNA-deficient, suggesting X-Y conjunction remains at these euchromatic sequences until anaphase I. From these previous observations, however, it was unclear if conjunction occurred directly at euchromatic sequences. To ask if pairing and conjunction of X euchromatin could occur completely independent of the rDNA, this study used fluorescent in situ hybridization to examine pairing between the X chromosome and Dp(1;3) chromosomes that contain a transposed segment of the X. As little as 120 kb of euchromatic homology was sufficient to ensure nearly complete pairing and could contribute to directing segregation. The ability to direct segregation was independent of the conjunction complex proteins Mod(mdg4)-in-meiosis and Teflon. It is concluded that pairing can occur at X euchromatin homologies, and these interactions may persist even in the absence of the conjunction complex and contribute to segregation of the paired elements to opposite spindle poles at meiosis I. | Meng, Z., Norwitz, N. G., Bickel, S. E. (2025). Meiotic cohesion requires Sirt1 and preserving its activity in aging oocytes reduces missegregation bioRxiv, PubMed ID: 40161738
Summary: Chromosome segregation errors in human oocytes increase dramatically as women age and premature loss of meiotic cohesion is one factor that contributes to a higher incidence of segregation errors in older oocytes. This study showed that cohesion maintenance during meiotic prophase in Drosophila oocytes requires the NAD(+)-dependent deacetylase, Sirt1. Knockdown of Sirt1 during meiotic prophase causes premature loss of arm cohesion and chromosome segregation errors. Previously work has demonstrated that when Drosophila oocytes arrest and age in diplotene, segregation errors increase significantly. By quantifying acetylation of the Sirt1 substrate H4K16 on oocytes chromosomes,this study found that Sirt1 deacetylase activity declines markedly during aging. However, if females are fed the Sirt1 activator SRT1720 as their oocytes age, the H4K16ac signal on oocyte DNA remains low in aged oocytes, consistent with preservation of Sirt1 activity during aging. Strikingly, age-dependent segregation errors are significantly reduced if mothers are fed SRT1720 while their oocytes age. These data suggest that maintaining Sirt1 activity in aging oocytes may provide a viable therapeutic strategy to decrease age-dependent segregation errors. |
| Hirai, K., Sakamoto, H., Keira, Y., Ozaki, M., Yamazoe, K., Ishikawa, H. O., Inoue, Y. H., Sawamura, K. (2025). The Drosophila nucleoporin ELYS is required for parental chromosome arrangement at fertilization G3 (Bethesda), 15(7) PubMed ID: 40359232
Summary: One key aspect of fertilization is the unification of the maternal and paternal genomes driven by the first mitotic spindle. However, little is known about the mechanisms that underlie the formation of a bipolar spindle that interacts with the two discrete chromosome sets in juxtaposition. This study showed that, in Drosophila, the maternally provided ELYS-an evolutionarily conserved subunit of the nuclear pore complex-localizes to female and male pronuclei and then redistributes to the interior of the spindle and the resulting zygotic nuclei. Both Elys loss-of-function mutations and ELYS overexpression in the female germline were associated with maternal-effect lethality. Cytological studies of fertilized eggs revealed that ELYS is primarily involved in the apposition of female and male pronuclei, potentially impacting the parental genome configuration of the first mitotic spindle. It is proposed that pronuclear apposition is essential for centrosome localization at the emergent pronuclear junction to promote bipolar spindle formation for the first mitosis. In addition,the possible involvement of ELYS in interspecific hybrid incompatibility is discussed. | Meng, X., Yamashita, Y. M. (2025). Intrinsically weak sex chromosome drive through sequential asymmetric meiosisSci Adv, 11(19):eadv7089 PubMed ID: 40333966
Summary: Meiotic drivers are selfish genetic elements that bias their own transmission, violating Mendel's Law of Equal Segregation. It has long been recognized that sex chromosome-linked drivers present a paradox: Their success in transmission can severely distort populations' sex ratio and lead to extinction. This paradox is typically solved by the presence of suppressors or fitness costs associated with the driver, limiting the propagation of the driver. This study shows that Stellate (Ste) in Drosophila melanogaster represents a novel class of X chromosome-linked driver that operates with an inherent mechanism that weakens its drive strength. Ste protein asymmetrically segregates into Y-bearing cells during meiosis I, subsequently causing their death. Unexpectedly, Ste segregates asymmetrically again during meiosis II, sparing half of the Y-bearing spermatids from Ste-induced defects, thereby weakening the drive strength. These findings reveal a mechanism by which sex chromosome drivers avoid suicidal success. |
Thursday April 2nd - Larval and adult neural development, structure and function |
| Jones, J. D., Holder, B. L., Montgomery, A. C., McAdams, C. V., He, E., Burns, A. E., Eiken, K. R., Vogt, A., Velarde, A. I., Elder, A. J., McEllin, J. A., Dissel, S. (2025). The dorsal fan-shaped body is a neurochemically heterogeneous sleep-regulating center in Drosophila PLoS Biol, 23(3):e3003014 PubMed ID: 40138668
Summary: Sleep is a behavior that is conserved throughout the animal kingdom. Yet, despite extensive studies in humans and animal models, the exact function or functions of sleep remain(s) unknown. In Drosophila, neurons projecting to the dorsal fan-shaped body (dFB) have been proposed to be key regulators of sleep, particularly sleep homeostasis. It was recently demonstrated that the most widely used genetic tool to manipulate dFB neurons, the 23E10-GAL4 driver, expresses in 2 sleep-regulating neurons (VNC-SP neurons) located in the ventral nerve cord (VNC), the fly analog of the vertebrate spinal cord. Since most data supporting a role for the dFB in sleep regulation have been obtained using 23E10-GAL4, it is unclear whether the sleep phenotypes reported in these studies are caused by dFB neurons or VNC-SP cells. A recent publication replicated the finding that 23E10-GAL4 contains sleep-promoting neurons in the VNC. However, it also proposed that the dFB is not involved in sleep regulation at all, but this suggestion was made using genetic tools that are not dFB-specific and a very mild sleep deprivation protocol. This study, using a newly created dFB-specific genetic driver line, demonstrated that optogenetic activation of the majority of 23E10-GAL4 dFB neurons promotes sleep and that these neurons are involved in sleep homeostasis. dFB neurons require stronger stimulation than VNC-SP cells to promote sleep. In addition, this study demonstrated that dFB-induced sleep can consolidate short-term memory (STM) into long-term memory (LTM), suggesting that the benefit of sleep on memory is not circuit-specific. Finally, this study showed that dFB neurons are neurochemically heterogeneous and can be divided in 3 populations. Most dFB neurons express both glutamate and acetylcholine, while a minority of cells expresses only one of these 2 neurotransmitters. Importantly, dFB neurons do not express GABA, as previously suggested. Using neurotransmitter-specific dFB tools, these data also points at cholinergic dFB neurons as particularly potent at regulating sleep and sleep homeostasis. | Ludke, A., Kumaraswamy, A., Galizia, C. G. (2025). Olfactory Receptor Responses to Pure Odorants in Drosophila melanogaster Eur J Neurosci, 61(5):e70036 PubMed ID: 40062376
Summary: Olfactory coding relies on primary information from olfactory receptor cells that respond to volatile airborne substances. Despite extensive efforts, understanding of odor-response profiles across receptors is still poor, because of the vast number of possible ligands (odorants), the high sensitivity even to trace compounds (creating false positive responses), and the diversity of olfactory receptors. This study linked chemical purification with a gas chromatograph to single-receptor type recording with transgenic flies using calcium imaging to record olfactory responses to a large panel of chemicals in seven Drosophila ORs: Or10a, Or13a, Or22a, Or42b, Or47a, Or56a, and Or92a. The data was analyzed using linear-nonlinear modeling and reveal that most receptors have "simple" response types (mostly positive: Or10a, Or13a, Or22a, Or47a, and Or56a). However, two receptors (Or42b and Or92a) have, in addition to "simple" responses, "complex" response types to some ligands, either positive with a negative second phase or negative with a positive second phase, suggesting the presence of multiple binding sites and/or transduction cascades. Some ligands reported in the literature are false positives, because of contaminations in the stimulus. All stimuli were recorded across concentrations, showing that at different concentrations, different substances appear as best ligands. The data show that studying combinatorial olfactory coding must consider temporal response properties and odorant concentration and, in addition, is strongly influenced by the presence of trace amounts of ligands (contaminations) in the samples. These observations have important repercussions for thinking about how animals navigate their olfactory environment. |
| Jiang, R., Tian, Y., Yuan, X., Guo, F. (2025). Regulation of pre-dawn arousal in Drosophila by a pair of trissinergic descending neurons of the visual and circadian networks Curr Biol, 35(8):1750-1764.e1753 PubMed ID: 40107265
Summary: Circadian neurons form a complex neural network that generates circadian oscillations. How the circadian neural network transmits circadian signals to other brain regions, thereby regulating the activity patterns in fruit flies, is not well known. Using the FlyWire database, this study identified a cluster of descending neurons, DNp27, which is densely connected with key circadian neurons and the visual circuit, projecting extensively across the brain. DNp27 receives excitatory inputs from the circadian neurons DN3s at night and photo-inhibitory signals predominantly during the day, resulting in calcium oscillations that peak in the early morning and dip at dusk. Experimental manipulation of DNp27 revealed its role in activity regulation: artificial activation of DNp27 decreased flies' activity, while ablation or silencing led to an advance in the morning anticipatory peak. Similar alterations in the morning peak were observed following pan-neuronal knockdown of either Trissin or TrissinR, suggesting the involvement of this neuropeptide signaling pathway in DNp27 function. Moreover, neural circuitry and connectivity analyses indicate that DNp27 may regulate circadian neurons via extra-clock electrical oscillators (xCEOs). Lastly, this study found that DNp27 modulates arousal thresholds by inhibiting light-responsive activity in the central brain, thereby promoting sleep stability, particularly in the pre-dawn period. Together, these findings suggest that DNp27 plays a crucial role in maintaining stable sleep patterns. | Lyu, C., Li, Z., Xu, C., Kalai, J., Luo, L. (2025). Rewiring an olfactory circuit by altering the combinatorial code of cell-surface proteins Res Sq, PubMed ID: 40162206
Summary: Proper brain function requires the precise assembly of neural circuits during development. Despite the identification of many cell-surface proteins (CSPs) that help guide axons to their targets, it remains largely unknown how multiple CSPs work together to assemble a functional circuit. This study used synaptic partner matching in the Drosophila circuitsolfactory receptor neuron (ORN) type, which senses a male pheromone that inhibits male-male courtship, its connection was switched from its endogenous postsynaptic projection neuron (PN) type nearly completely to a new PN type that promotes courtship. To achieve this switch, a combinatorial code including CSPs was deduced that mediate both attractive and repulsive interactions between synaptic partners. The deduced anatomical switch changed the odor response of the new PN partner and markedly increased male-male courtship. Three manipulation strategies were generalized from this rewiring to successfully rewire a second ORN type to multiple distinct PN types. This work demonstrates that manipulating a small set of CSPs is sufficient to respecify synaptic connections, paving ways to explore how neural systems evolve through changes of circuit connectivity. |
| Li, Z., Lyu, C., Xu, C., Hu, Y., Luginbuhl, D. J., Lehovic, A. B., Priest, J. M., Ozkan, E., Luo, L. (2025). Repulsive interactions instruct synaptic partner matching in an olfactory circuit Res Sq, PubMed ID: 40162214
Summary: Neurons exhibit extraordinary precision in selecting synaptic partners. Whereas cell-surface proteins (CSPs) mediating attractive interactions between developing axons and dendrites have been shown to instruct synaptic partner matching, it is less clear the degree to which repulsive interactions play a role. Using a genetic screen guided by single cell transcriptomes, this study identified three CSP pairs-Toll2-Ptp10D, Fili-Kek1, and Hbs/Sns-Kirre-in mediating repulsive interactions between non-partner olfactory receptor neuron (ORN) axons and projection neuron (PN) dendrites in the developing Drosophila olfactory circuit. Each CSP pair exhibits inverse expression patterns in the select PN-ORN partners. Loss of each CSP in ORNs led to similar synaptic partner matching deficits as the loss of its partner CSP in PNs, and mistargeting phenotypes caused by overexpressing one CSP could be suppressed by loss of its partner CSP. Each CSP pair is also differentially expressed in other brain regions. Together, these data reveal that multiple repulsive CSP pairs work together to ensure precise synaptic partner matching during development by preventing neurons from forming connections with non-cognate partners. | Kautzmann, S., Rey, S., Krebs, A., Klambt, C. (2025). Cholinergic and Glutamatergic Axons Differentially Require Glial Support in the Drosophila PNS Glia, 73(7):1365-1382 PubMed ID: 40097245
Summary: In vertebrates, there is a differential interaction between peripheral axons and their associated glial cells. While large-caliber axons are covered by a myelin sheath, small-diameter axons are simply wrapped in Remak fibers. In peripheral nerves of Drosophila larvae, axons are covered by wrapping glial cell processes similar to vertebrate Remak fibers. Whether differences in axonal diameter influence the interaction with glial processes in Drosophila has not yet been analyzed. Likewise, it is not understood whether the modality of the neuron affects the interaction with the wrapping glia. To start to decipher the mechanisms underlying glial wrapping, this study employed APEX2 labeling in larval filet preparations. This allowed following of individual axons of defined segmental nerves at ultrastructural resolution in the presence or absence of wrapping glia. Using these tools, it was first demonstrated that motor axons are larger compared to sensory axons. Sensory axons fasciculate in larger groups than motor axons, suggesting that they do not require direct contact with wrapping glia. However, unlike motor axons, sensory axons show length-dependent degeneration upon ablation of wrapping glia. These data suggest that Drosophila may help to understand peripheral neuropathies caused by defects in Schwann cell function, in which a similar degeneration of sensory axons is observed. |
Wednesday April 1st - Larval and adult development |
| Carrillo, J. A., Murakawa, H., Sato, M., Wang, M. (2025). A new paradigm considering multicellular adhesion, repulsion and attraction represent diverse cellular tile patterns PLoS Comput Biol, 21(4):e1011909 PubMed ID: 40258228
Summary: Cell sorting by differential adhesion is one of the basic mechanisms explaining spatial organization of neurons in early stage brain development of fruit flies. The columnar arrangements of neurons determine the large-scale patterns in the fly visual center. Experimental studies indicate that hexagonal configurations regularly appear in the fly compound eye, which is connected to the visual center by photoreceptor axons, while tetragonal configurations can be induced in mutants. A mathematical framework is needed to study the mechanisms of such a transition between hexagonal and tetragonal arrangements. This study proposes a new mathematical model based on macroscopic approximations of agent-based models that produces a similar behavior changing from hexagonal to tetragonal steady configurations when medium-range repulsion and longer-range attraction between individuals are incorporated in previous successful models for cell sorting based on adhesion and volume constraints. The angular configurations of these patterns was analyzed based on angle summary statistics and experimental data and parameter fitted ARA (Adhesion-Repulsion-Attraction) models showing that intermediate patterns between hexagonal and tetragonal configuration are common in experimental data as well as in the ARA mathematical model. These studies indicate an overall qualitative agreement of ARA models in tile patterning and pave the way for their quantitative studies. This study opens up a new avenue to explore tile pattern transitions, found not only in the column arrangement in the brain, but also in the other related biological processes. | Alber, D. S., Zhao, S., Jacinto, A. O., Wieschaus, E. F., Shvartsman, S. Y., Haas, P. A. (2025). A model for boundary-driven tissue morphogenesis ArXiv, PubMed ID: 40093362
Summary: Tissue deformations during morphogenesis can be active, driven by internal processes, or passive, resulting from stresses applied at their boundaries. This study introduces the Drosophila hindgut primordium as a model for studying boundary-driven tissue morphogenesis. Its deformations were characterized and its complex shape changes can be a passive consequence of the deformations of the active regions of the embryo that surround it. First, an intermediate characteristic triangular shape was found in the 3D deformations of the hindgut. A minimal model of the hindgut primordium was constructed as an elastic ring deformed by active midgut invagination and germ band extension on an ellipsoidal surface, which robustly captures the symmetry-breaking into this triangular shape. The 3D kinematics of the tissue were quantified by a set of contours, and dthe hindgut was found to deform in two stages: an initial translation on the curved embryo surface followed by a rapid breaking of shape symmetry. This model was extended to show that the contour kinematics in both stages are consistent with the passive picture. These results suggest that the role of in-plane deformations during hindgut morphogenesis is to translate the tissue to a region with anisotropic embryonic curvature and show that uniform boundary conditions are sufficient to generate the observed nonuniform shape change. This work thus provides a possible explanation for the various characteristic shapes of blastopore-equivalents in different organisms and a framework for the mechanical emergence of global morphologies in complex developmental systems. |
| Lee, J. I., Park, S., Park, H., Lee, Y., Park, J., Lee, D., Kim, M. J., Choe, K. M. (2025). The matrix glycoprotein Papilin maintains the haematopoietic progenitor pool in Drosophila lymph glands Development, 152(7) PubMed ID: 40094323
Summary: Differentiation of prohaemocytes, the precursors of Drosophila blood cells (haemocytes), and the release of haemocytes from the lymph gland, a major larval haematopoietic organ, are vital responses to wasp infestation or tissue degeneration. Although cells and extracellular mlllllix (ECM) in the lymph gland are known to play a crucial role in haemocyte differentiation, the underlying mechanisms remain unclear. This study shows that the matrix glycoprotein Papilin (Ppn) is essential for maintaining the prohaemocyte population in lymph glands. In Ppn-depleted larvae, haemocyte differentiation increased with a reduction in the prohaemocyte-containing medullary zone, and lymph gland lobes dispersed prematurely. Ppn was synthesised by plasmatocytes, forming lamellae mainly in the medullary zone. Microbial infection or wasp infestation disrupted the Ppn meshwork within lymph glands. Ppn colocalised with collagen, laminin, nidogen and perlecan. Ppn depletion disrupted the ECM structure, including perlecan organisation. Phenotypes caused by Ppn depletion were partially rescued by perlecan overexpression or inactivation of the epidermal growth factor receptor pathway. Thus, Ppn is crucial for maintaining lymph gland architecture and regulating haemocyte differentiation, highlighting an intricate interaction between the ECM and signalling pathways in haematopoiesis. | Marcetteau, J., Duarte, P., Leitao, A. B., Sucena, E. (2025). Transdifferentiation of plasmatocytes to crystal cells in the lymph gland of Drosophila melanogaster EMBO Rep, 26(8):2077-2097 PubMed ID: 40075235
Summary: Under homeostatic conditions, haematopoiesis in Drosophila larvae occurs in the lymph gland and sessile haemocyte clusters to produce two functionally and morphologically different cells: plasmatocytes and crystal cells. It is well-established that in the lymph gland both cell types stem from a binary decision of the medullary prohaemocyte precursors. However, in sessile clusters and dorsal vessel, crystal cells have been shown to originate from the transdifferentiation of plasmatocytes in a Notch/Serrate-dependent manner. This study show shows that transdifferentiation occurs also in the lymph gland. In vivo phagocytosis assays confirm that cortical plasmatocytes are functionally differentiated phagocytic cells. A double-positive population in the cortical zone was uncovered that lineage-tracing and long-term live imaging experiments show will differentiate into crystal cells. The reduction of Notch levels within the lymph gland plasmatocyte population reduces crystal cell number. This extension of a transdifferentiation mechanism reinforces the growing role of haematopoietic plasticity in maintaining homeostasis in Drosophila and vertebrate systems. Future work should test the regulation and relative contribution of these two processes under different immunological and/or metabolic conditions. |
| Lee, T., Kim, C. J., Lim, D. H., Lee, Y. S. (2025). microRNA miR-315-5p regulates developmental growth in Drosophila wings by targeting S6k Insect Sci, PubMed ID: 40166978
Summary: Tissue growth in Drosophila is regulated by various factors, with microRNAs (miRNAs) emerging as key players over the past decade. However, the precise roles of miRNAs in growth regulation remain incompletely understood. This study explored the biological role of miR-315 in wing growth regulation. Inhibition of miR-315-5p activity using a miR-315 sponge led to an increase in wing size, whereas its overexpression resulted in reduced wing size, primarily through a decrease in wing cell size. Ribosomal protein kinase p-70-S6k (S6k) was identified as a target of miR-315-5p in relation to wing growth control. Overexpression of miR-315 reduced both total S6k and phosphorylated S6k protein levels in Drosophila S2 cells and wing discs. Additionally, a luciferase reporter assay confirmed that miR-315-5p directly binds to the 3'-untranslated region of S6k. Consistently, RNAi-mediated depletion of S6k led to smaller wings, primarily due to a reduction in cell size. Notably, co-overexpression of active S6k rescued the wing defects caused by miR-315 overexpression. Overall, these findings demonstrate that miR-315 regulates wing growth by suppressing S6k expression. | Delage, S., Zadhoosh, A., You, W., Brown, T. J., Ringuette, M. J. (2025). Drosophila SPARC collagen IV chaperone-like activity essential for development is unique to the fat body iScience, 28(4):112111 PubMed ID: 40241767
Summary: Drosophila fat body-derived SPAR acts as a chaperone for collagen IV (Col(IV)), enabling their diffusion and incorporation into distal tissue basement membranes (BMs). Disruption of SPARC or Col(IV) production by the fat body is lethal, despite expression by other tissues such as imaginal discs. Wing disc-derived SPARC does not associate with Col(IV) in BMs and is not essential for survival. Differential association of fat body- and wing disc-derived SPARC with Col(IV) is not due to differences in SPARC glycosylation nor to the absence of SPARC and Col(IV) co-expression. Further, SPARC domain II/III produced by the fat body is sufficient for Col(IV) diffusion to both proximal and distal BMs, and rescues lethality associated with loss of SPARC. However, SPARC domain II/III does not diffuse beyond the hemolymph. Thus, the essential Col(IV) chaperone-like activity specific to fat body-derived SPARC is not required beyond the hemolymph. |
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