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Current papers in developmental biology and gene function
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May 2025
April 2025 March 2025 February 2025 January 2025 December 2024 November 2024 October 2024 September 2024 August 2024 July 2024 June 2024 May 2024 April 2024 March 2024 February 2024 January 2024 December 2023 November 2023 October 2023 September 2023 August 2023 July 2023 June 2023 December 2022 December 2021 December 2020 December 2019 December 2018 | Kaul, N., Pradhan, S. J., Boin, N. G., Mason, M. M., Rosales, J., Starke, E. L., Wilkinson, E. C., Chapman, E. G., Barbee, S. A. (2024). FMRP cooperates with miRISC components to repress translation and regulate neurite morphogenesis in Drosophila. RNA Biol, 21(1):11-22 PubMed ID: 39190491
Summary: Fragile X Syndrome (FXS) is the most common inherited form of intellectual disability and is caused by mutations in the gene encoding the Fragile X messenger ribonucleoprotein (FMRP). FMRP is an evolutionarily conserved and neuronally enriched RNA-binding protein (RBP) with functions in RNA editing, RNA transport, and protein translation. Specific target RNAs play critical roles in neurodevelopment, including the regulation of neurite morphogenesis, synaptic plasticity, and cognitive function. The different biological functions of FMRP are modulated by its cooperative interaction with distinct sets of neuronal RNA and protein-binding partners. This study focused on interactions between FMRP and components of the microRNA (miRNA) pathway. Using the Drosophila S2 cell model system, this study showed that the Drosophila ortholog of FMRP (dFMRP) can repress translation when directly tethered to a reporter mRNA. This repression requires the activity of AGO1, GW182, and MOV10/Armitage, conserved proteins associated with the miRNA-containing RNA-induced silencing complex (miRISC). Additionally, untagged dFMRP can interact with a short stem-loop sequence in the translational reporter, a prerequisite for repression by exogenous miR-958. Finally, dFmr1 interacts genetically with GW182 to control neurite morphogenesis. These data suggest that dFMRP may recruit the miRISC to nearby miRNA binding sites and repress translation via its cooperative interactions with evolutionarily conserved components of the miRNA pathway. | He, Q., Chen, S., Hou, T., Chen, J. (2024). Juvenile hormone-induced microRNA miR-iab-8 regulates lipid homeostasis and metamorphosis in Drosophila melanogaster. Insect Mol Biol, PubMed ID: 39005109
Summary: Metamorphosis plays an important role in the evolutionary success of insects. Accumulating evidence indicated that microRNAs (miRNAs) are involved in the regulation of processes associated with insect metamorphosis. However, the miRNAs coordinated with juvenile hormone (JH)-regulated metamorphosis remain poorly reported. In the present study, using high-throughput miRNA sequencing combined with Drosophila genetic approaches, it was demonstrated that miR-iab-8, which primarily targets homeotic genes to modulate haltere-wing transformation and sterility was up-regulated by JH and involved in JH-mediated metamorphosis. Overexpression of miR-iab-8 in the fat body resulted in delayed development and failure of larval-pupal transition. Furthermore, metabolomic analysis results revealed that overexpression of miR-iab-8 caused severe energy metabolism defects especially the lipid metabolism, resulting in significantly reduced triacylglycerol (TG) content and glycerophospholipids but enhanced accumulation of phosphatidylcholine (PC) and phosphatidylethanolamine (PE). In line with this, Nile red staining demonstrated that during the third larval development, the TG content in the miR-iab-8 overexpression larvae was continuously decreased, which is opposite to the control. Additionally, the transcription levels of genes committed to TG synthesis and breakdown were found to be significantly increased and the expression of genes responsible for glycerophospholipids metabolism were also altered. Overall, it is proposed that JH induced miR-iab-8 expression to perturb the lipid metabolism homeostasis especially the TG storage in the fat body, which in turn affected larval growth and metamorphosis. |
| Zhang, Q., Li, L., Zhang, Q., Zhang, Y., Yan, L., Wang, Y., Wang, Y., Zhao, S. (2024). Genetic circuitry controlling Drosophila female germline overgrowth. Dev Biol, 515:160-168 PubMed ID: 39067502
Summary: Germ cells mutant for bam or bgcn are locked in a germline stem cell (GSC)-like state, leading to tumor-like overgrowth in Drosophila ovaries. Previous studies have demonstrated that germline overgrowth in bam mutants can be suppressed by defects in the miRNA pathway but enhanced by a null mutation in hippo. However, the genetic epistasis between the miRNA and Hippo pathways still remains unknown. Here, we determined that the miRNA pathway acts downstream of the Hippo pathway in regulating this process. Germ cells mutant for bam or bgcn and defective in both pathways divide very slowly, phenocopying those defective only in the miRNA pathway. In addition, we found that Yki, a key oncoprotein in the Hippo pathway, promotes the growth of both wild-type germ cells and bam mutant GSC-like cells. Like wild-type GSCs, bam mutant GSC-like cells predominantly stay in the G2 phase. Remarkably, many of those defective in the miRNA pathway are arrested before entering this phase. Furthermore, these studies identified bantam as a critical miRNA promoting germline overgrowth in bam or bgcn mutants. Taken together, these findings establish a genetic circuitry controlling Drosophila female germline overgrowth. | Li, Z., Iida, J., Shiimori, M., Okamura, K. (2024). Exportin-5 binding precedes 5'- and 3'-end processing of tRNA precursors in Drosophila. J Biol Chem, 300(9):107632 PubMed ID: 39098529
Summary: Exportin5 (Exp5) is the major miRNA nuclear export factor and recognizes structural features of pre-miRNA hairpins, while it also exports other minihelix-containing RNAs. In Drosophila, Exp5 is suggested to play a major role in tRNA export because the gene encoding the canonical tRNA export factor Exportin-t is missing in its genome. To understand molecular functions of fly Exp5, the Exp5/RNA interactome was studied in the cell line S2R + using the crosslinking and immunoprecipitation (CLIP) technology. The CLIP experiment captured known substrates such as tRNAs and miRNAs and detected candidates of novel Exp5 substrates including various mRNAs and long non-coding RNAs (lncRNAs). Some mRNAs and lncRNAs enriched PAR-CLIP tags compared to their expression levels, suggesting selective binding of Exp5 to them. Intronless mRNAs tended to enrich PAR-CLIP tags; therefore, it was proposed that Exp5 might play a role in the export of specific classes of mRNAs/lncRNAs. This result suggested that Drosophila Exp5 might have a wider variety of substrates than initially thought. Surprisingly, Exp5 CLIP reads often contained sequences corresponding to the flanking 5'-leaders and 3'-trailers of tRNAs, which were thought to be removed prior to nuclear export. In fact, pre-tRNAs before end-processing were present in the cytoplasm, supporting the idea that tRNA end-processing is a cytoplasmic event. In summary, theseresults provide a genome-wide list of Exp5 substrate candidates and suggest that flies may lack a mechanism to distinguish pre-tRNAs with or without the flanking sequences. |
| Mostoufi, S. L., Singh, N. D. (2024)s. Pathogen infection alters the gene expression landscape of transposable elements in Drosophila melanogaster. G3 (Bethesda), 14(9) PubMed ID: 39129654
Summary: Transposable elements make up substantial proportions of eukaryotic genomes, and many are thought to be remnants of ancient viral infections. Current research has begun to highlight the role transposable elements can play in the immune system response to infections. However, most of our knowledge about transposable element expression during infection is limited by the specific host and pathogen factors from each study, making it difficult to compare studies and develop broader patterns regarding the role of transposable elements during infection. This study used the tools and resources available in the model, Drosophila melanogaster, to analyze multiple gene expression datasets of flies subject to bacterial, fungal, and viral infections. Differences in pathogen species, host genotype, host tissue, and sex were analyzed to understand how these factors impact transposable element expression during infection. The results highlight both shared and unique transposable element expression patterns between pathogens and suggest a larger effect of pathogen factors over host factors for influencing transposable element expression. | Chen, R., Stainier, W., Dufourt, J., Lagha, M., Lehmann, R. (2024). Direct observation of translational activation by a ribonucleoprotein granule. Nat Cell Biol, 26(8):1322-1335 PubMed ID: 38965420
Summary: Biomolecular condensates organize biochemical processes at the subcellular level and can provide spatiotemporal regulation within a cell. Among these, ribonucleoprotein (RNP) granules are storage hubs for translationally repressed mRNA. Whether RNP granules can also activate translation and how this could be achieved remains unclear. Using single-molecule imaging, this study demonstrated that the germ cell-determining RNP granules in Drosophila embryos are sites for active translation of nanos mRNA. Nanos translation occurs preferentially at the germ granule surface with the 3' UTR buried within the granule. Smaug, a cytosolic RNA-binding protein, represses nanos translation, which is relieved when Smaug is sequestered to the germ granule by the scaffold protein Oskar. Together, these findings uncover a molecular process by which RNP granules achieve localized protein synthesis through the compartmentalized loss of translational repression. |
Thursday June 26th - Larval and Adult Neural Development, Structure and Function |
| Zhu, J., Boivin, J. C., Garner, A., Ning, J., Zhao, Y. Q., Ohyama, T. (2024). Feedback inhibition by a descending GABAergic neuron regulates timing of escape behavior in Drosophila larvae. Elife, 13 PubMed ID: 39196635
Summary: Escape behaviors help animals avoid harm from predators and other threats in the environment. Successful escape relies on integrating information from multiple stimulus modalities (of external or internal origin) to compute trajectories toward safe locations, choose between actions that satisfy competing motivations, and execute other strategies that ensure survival. To this end, escape behaviors must be adaptive. When a Drosophila melanogaster larva encounters a noxious stimulus, such as the focal pressure a parasitic wasp applies to the larval cuticle via its ovipositor, it initiates a characteristic escape response. The escape sequence consists of an initial abrupt bending, lateral rolling, and finally rapid crawling. Previous work has shown that the detection of noxious stimuli primarily relies on class IV multi-dendritic arborization neurons (Class IV neurons) located beneath the body wall, and more recent studies have identified several important components in the nociceptive neural circuitry involved in rolling. However, the neural mechanisms that underlie the rolling-escape sequence remain unclear. This study presents both functional and anatomical evidence suggesting that bilateral descending neurons within the subesophageal zone of D. melanogaster larva play a crucial role in regulating the termination of rolling and subsequent transition to escape crawling. These descending neurons (designated SeIN128) are inhibitory and receive inputs from a second-order interneuron upstream (Basin-2) and an ascending neuron downstream of Basin-2. Together with optogenetic experiments showing that co-activation of SeIN128 neurons and Basin-2 influence the temporal dynamics of rolling, these findings collectively suggest that the ensemble of SeIN128, Basin-2, and A00c neurons forms a GABAergic feedback loop onto Basin-2, which inhibits rolling and thereby facilitates the shift to escape crawling. | Chu, L. A., Tai, C. Y., Chiang, A. S. (2024). Thirst-driven hygrosensory suppression promotes water seeking in Drosophila. Proc Natl Acad Sci U S A, 121(34):e2404454121 PubMed ID: 39145936
Summary: Survival in animals relies on navigating environments aligned with physiological needs. In Drosophila melanogaster, antennal ionotropic receptors (IRs) sensing humidity changes govern hygrotaxis behavior. This study sheds light on the crucial role of R8a neurons in the transition from high humidity avoidance to water-seeking behavior when the flies become thirsty. These neurons demonstrate a heightened calcium response toward high humidity stimuli in satiated flies and a reduced response in thirsty flies, modulated by fluctuating levels of the neuropeptide leucokinin, which monitors the internal water balance. Optogenetic activation of IR8a neurons in thirsty flies triggers an avoidance response similar to the moisture aversion in adequately hydrated flies. Furthermore, this study identifies IR40a neurons as associated with dry avoidance, while IR68a neurons are linked to moist attraction. The dynamic interplay among these neurons, each with opposing valences, establishes a preference for approximately 30% relative humidity in well-hydrated flies and facilitates water-seeking behavior in thirsty individuals. This research unveils the intricate interplay between sensory perception, neuronal plasticity, and internal states, providing valuable insights into the adaptive mechanisms governing hygrotaxis in Drosophila. |
| Zhao, Q., Li, X., Wen, J., He, Y., Zheng, N., Li, W., Cardona, A., Gong, Z. (2024). A two-layer neural circuit controls fast forward locomotion in Drosophila. Curr Biol, 34(15):3439-3453 PubMed ID: 39053465
Summary: Fast forward locomotion is critical for animal hunting and escaping behaviors. However, how the underlying neural circuit is wired at synaptic resolution to decide locomotion direction and speed remains poorly understood. This study identified in the ventral nerve cord (VNC) a set of ascending cholinergic neurons (AcNs) to be command neurons capable of initiating fast forward peristaltic locomotion in Drosophila larvae. Targeted manipulations revealed that AcNs are necessary and sufficient for fast forward locomotion. AcNs can activate their postsynaptic partners, A01j and A02j; both are interneurons with locomotory rhythmicity. Activated A01j neurons form a posterior-anteriorly descendent gradient in output activity along the VNC to launch forward locomotion from the tail. Activated A02j neurons exhibit quicker intersegmental transmission in activity that enables fast propagation of motor waves. This work revealed a global neural mechanism that coordinately controls the launch direction and propagation speed of Drosophila locomotion, furthering the understanding of the strategy for locomotion control. | Lehman, M., Barre, C., Hasan, M. A., Flament, B., Autran, S., Dhiman, N., Soba, P., Masson, J. B., Jovanic, T. (2025). Neural circuits underlying context-dependent competition between defensive actions in Drosophila larvae. Nat Commun, 16(1):1120 PubMed ID: 39875414
Summary: To ensure their survival, animals must be able to respond adaptively to threats within their environment. However, the precise neural circuit mechanisms that underlie flexible defensive behaviors remain poorly understood. Using neuronal manipulations, machine learning-based behavioral detection, electron microscopy (EM) connectomics and calcium imaging in Drosophila larvae, this study mapped second-order interneurons that are differentially involved in the competition between defensive actions in response to competing aversive cues. Mechanosensory stimulation inhibits escape behaviors in favor of startle behaviors by influencing the activity of escape-promoting second-order interneurons. Stronger activation of those neurons inhibits startle-like behaviors. This suggests that competition between startle and escape behaviors occurs at the level of second-order interneurons. Finally, a pair of descending neurons was identified that promote startle behaviors and could modulate the escape sequence. Taken together, these results characterize the pathways involved in startle and escape competition, which is modulated by the sensory context. |
| Shiozaki, H. M., Wang, K., Lillvis, J. L., Xu, M., Dickson, B. J., Stern, D. L. (2024). Activity of nested neural circuits drives different courtship songs in Drosophila. Nat Neurosci, PubMed ID: 39198658
Summary: Motor systems implement diverse motor programs to pattern behavioral sequences, yet how different motor actions are controlled on a moment-by-moment basis remains unclear. This study investigated the neural circuitcourtship songs in Drosophila. Courting males rapidly alternate between two types of song: pulse and sine. By recording calcium signals in the ventral nerve cord in singing flies, one neural population was found to be active during both songs, whereas an expanded neural population, which includes neurons from the first population, is active during pulse song. Brain recordings showed that this nested activation pattern is present in two descending pathways required for singing. Connectomic analysis reveals that these two descending pathways provide structured input to ventral nerve cord neurons in a manner consistent with their activation patterns. These results suggest that nested premotor circuit activity, directed by distinct descending signals, enables rapid switching between motor actions. | Prieto, D., Egger, B., Cantera, R. (2024). Atypical soluble guanylyl cyclases control brain size in Drosophila. . microPublication biology, 2024. PubMed ID: 39185012
Summary: Hypoxia-induced proliferation of neural stem cells has a crucial role in brain development. In the brain of Drosophila melanogaster, the optic lobe exhibits progressive hypoxia during larval development. This study investigated an alternative oxygen-sensing mechanism within this brain compartment, distinct from the canonical hypoxia signaling pathway mediated by HIF. Using genetic tools, immunostaining, and confocal microscopy, the loss of the atypical soluble guanylyl cyclase (asGC) subunit Gyc88E, or the ectopic expression of Gyc89Db in neural stem cells was shown to lead to increased optic lobe volume. The existence of a link between cGMP signaling and neurogenesis in the developing brain is proposed. |
Wednesday June 25th - Adult Development |
| Zhang, X., Wang, Y., Zhao, W., Yang, S., Moussian, B., Zhao, Z., Zhang, J., Dong, W. (2024). Excess Dally-like Induces Malformation of Drosophila Legs. Cells, 13(14) PubMed ID: 39056781
Summary: Glypicans are closely associated with organ development and tumorigenesis in animals. Dally-like (Dlp), a membrane-bound glypican, plays pivotal roles in various biological processes in Drosophila. This study observed that an excess of Dlp led to the malformation of legs, particularly affecting the distal part. Accordingly, the leg disc was shrunken and frequently exhibited aberrant morphology. In addition, elevated Dlp levels induced ectopic cell death with no apparent cell proliferation changes. Furthermore, Dlp overexpression in the posterior compartment significantly altered Wingless (Wg) distribution. A marked expansion of Wg distribution was observed within the posterior compartment, accompanied by a corresponding decrease in the anterior compartment. It appears that excess Dlp guides Wg to diffuse to cells with higher Dlp levels. In addition, the distal-less (dll) gene, which is crucial for leg patterning, was up-regulated significantly. Notably, dachshund (dac) and homothorax (hth) expression, also essential for leg patterning and development, only appeared to be negligibly affected. Based on these findings, it is speculated that excess Dlp may contribute to malformations of the distal leg region of Drosophila, possibly through its influence on Wg distribution, dll expression and induced cell death. Our research advances the understanding of Dlp function in Drosophila leg development. | Walther, R. F., Lancaster, C., Burden, J. J., Pichaud, F. (2024). A dystroglycan-laminin-integrin axis coordinates cell shape remodeling in the developing Drosophila retina. PLoS Biol, 22(9):e3002783 PubMed ID: 39226305
Summary: Cell shape remodeling is a principal driver of epithelial tissue morphogenesis. While progress continues to be made in our understanding of the pathways that control the apical (top) geometry of epithelial cells, comparatively little is known about those that control cell basal (bottom) geometry. To examine this, the Drosophila ommatidium, which is the basic visual unit of the compound eye, was used. The ommatidium is shaped as a hexagonal prism, and generating this 3D structure requires ommatidial cells to adopt specific apical and basal polygonal geometries. Using this model system generating cell type-specific basal geometries was found to start with patterning of the basal extracellular matrix, whereby Laminin<>/a> accumulates at discrete locations across the basal surface of the retina. The Dystroglycan receptor complex (DGC) is required for this patterning by promoting localized Laminin accumulation at the basal surface of cells. Moreover, the results reveal that localized accumulation of Laminin and the DGC are required for directing Integrin adhesion. This induces cell basal geometry remodeling by anchoring the basal surface of cells to the extracellular matrix at specific, Laminin-rich locations. It is proposed that patterning of a basal extracellular matrix by generating discrete Laminin domains can direct Integrin adhesion to induce cell shape remodeling in epithelial morphogenesis. |
| Teeters, G., Weasner, B. M., Ordway, A. J., Weasner, B. P., Kumar, J. P. (2024). Control of fate specification within the dorsal head of Drosophila melanogaster. Development, 151(16) PubMed ID: 39190554
Summary: During development, unique combinations of transcription factors and signaling pathways carve the nascent eye-antennal disc of the fruit fly Drosophila melanogaster into several territories that will eventually develop into the compound eye, ocelli, head epidermis, bristles, antenna and maxillary palpus of the adult head. Juxtaposed patterns of Hedgehog (Hh) and Decapentaplegic (Dpp) initiate compound eye development, while reciprocal domains of Dpp and Wingless (Wg) induce formation of the antennal and maxillary palp fields. Hh and Wg signaling, but not Dpp, contribute to the patterning of the dorsal head vertex. This study shows that combinatorial reductions of the Pax6 transcription factor Twin of Eyeless and either the Wg pathway or the Mirror (Mirr)z transcription factor trigger a transformation of the ocelli into a compound eye and the neighboring head epidermis into an antenna. These changes in fate are accompanied by the ectopic expression of Dpp, which might be expected to trigger these changes in fate. However, the transformation of the field cannot be replicated by increasing Dpp levels alone despite the recreation of adjacent Hh-Dpp and Wg-Dpp domains. As such, the emergence of these ectopic organs occurs through a unique regulatory path. | Ehrhardt, B., Angstmann, H., Hoschler, B., Kovacevic, D., Hammer, B., Roeder, T., Rabe, K. F., Wagner, C., Uliczka, K., Krauss-Etschmann, S. (2024). Airway specific deregulation of asthma-related serpins impairs tracheal architecture and oxygenation in D. melanogaster. Sci Rep, 14(1):16567 PubMed ID: 39019933
Summary: Serine proteases are important regulators of airway epithelial homeostasis. Altered serum or cellular levels of two serpins, Scca1 and Spink5, have been described for airway diseases but their function beyond antiproteolytic activity is insufficiently understood. To close this gap, fly lines were generated with overexpression or knockdown for each gene in the airways. Overexpression of both fly homologues of Scca1 (Spn42DdCG32354) induced the growth of additional airway branches, with more variable results for the respective knockdowns. Dysregulation of Scca1 resulted in a general delay in fruit fly development, with increases in larval and pupal mortality following overexpression of this gene. In addition, the morphological changes in the airways were concomitant with lower tolerance to hypoxia. In conclusion, the observed structural changes of the airways evidently had a strong impact on the airway function in our model as they manifested in a lower physical fitness of the animals. We assume that this is due to insufficient tissue oxygenation. Future work will be directed at the identification of key molecular regulators following the airway-specific dysregulation of Scca1 and Spink5 expression. |
| Hiraiwa, S., Takeshita, S., Terano, T., Hayashi, R., Suzuki, K., Tajiri, R., Kojima, T. (2024). Unveiling the cell dynamics during the final shape formation of the tarsus in Drosophila adult leg by live imaging. Dev Genes Evol, PubMed ID: 38977431
Summary: Organisms display a remarkable diversity in their shapes. Although substantial progress has been made in unraveling the mechanisms that govern cell fate determination during development, the mechanisms by which fate-determined cells give rise to the final shapes of organisms remain largely unknown. This study describes in detail the process of the final shape formation of the tarsus, which is near the distal tip of the adult leg, during the pupal stage in Drosophila melanogaster. Days-long live imaging revealed unexpectedly complicated cellular dynamics. The epithelial cells transiently form the intriguing structure, which was named the Parthenon-like structure. The basal surface of the epithelial cells and localization of the basement membrane protein initially show a mesh-like structure and rapidly shrink into the membranous structure during the formation and disappearance of the Parthenon-like structure. Furthermore, macrophage-like cells are observed moving around actively in the Parthenon-like structure and engulfing epithelial cells. The findings in this research are expected to significantly contribute to our understanding of the mechanisms involved in shaping the final structure of the adult tarsus. | Fuhrmann, J. F., Krishna, A., Paijmans, J., Duclut, C., Cwikla, G., Eaton, S., Popovic, M., Julicher, F., Modes, C. D., Dye, N. A. (2024). Active shape programming drives Drosophila wing disc eversion. Sci Adv, 10(32):eadp0860 PubMed ID: 39121221
Summary: How complex 3D tissue shape emerges during animal development remains an important open question in biology and biophysics. This study discovered a mechanism for 3D epithelial shape change based on active, in-plane cellular events that is analogous to inanimate "shape programmable" materials, which undergo blueprinted 3D shape transformations from in-plane gradients of spontaneous strains. Eversion of the Drosophila wing disc pouch, when the epithelium transforms from a dome into a curved fold, quantifying 3D tissue shape changes and mapping spatial patterns of cellular behaviors on the evolving geometry using cellular topology. Using a physical model inspired by shape programming, active cell rearrangements were found that are the major contributor to pouch eversion and validate this conclusion using a knockdown of MyoVI, which reduces rearrangements and disrupts morphogenesis. This work shows that shape programming is a mechanism for animal tissue morphogenesis and suggests that patterns in nature could present design strategies for shape-programmable materials. |
Tuesday June 24th - Signaling |
| Nair, S., Baker, N. E. (2024). Extramacrochaetae regulates Notch signaling in the Drosophila eye through non-apoptotic caspase activity. bioRxiv, PubMed ID: 39131389
Summary: Many cell fate decisions are determined transcriptionally. Accordingly, some fate specification is prevented by Inhibitor of DNA binding (Id) proteins that interfere with DNA binding by master regulatory transcription factors. The Drosophila Id protein Extra macrochaetae (Emc) also affect developmental decisions by regulating caspase activity. Emc, which prevents proneural bHLH transcription factors from specifying neural cell fate, also prevents homodimerization of another bHLH protein, Daughterless (Da), and thereby maintains expression of the Death-Associated Inhibitor of Apoptosis (diap1) gene. Multiple effects of emc mutations on cell growth and on eye development were all caused by reduced Diap1 levels and corresponding activation of caspases. These effects included acceleration of the morphogenetic furrow, failure of R7 photoreceptor cell specification, and delayed differentiation of non-neuronal cone cells. Within emc mutant clones, Notch signaling was elevated in the morphogenetic furrow, increasing morphogenetic furrow speed. This was associated with caspase-dependent increase in levels of Delta protein, the transmembrane ligand for Notch. Posterior to the morphogenetic furrow, elevated Delta cis-inhibited Notch signaling that was required for R7 specification and cone cell differentiation. Thus, emc mutations reveal the importance of restraining caspase activity even in non-apoptotic cells to prevent abnormal development, in the Drosophila eye through effects on Notch signaling. | Ewen-Campen, B., Perrimon, N. (2024). Wnt signaling modulates the response to DNA damage in the Drosophila wing imaginal disc by regulating the EGFR pathway. PLoS Biol, 22(7):e3002547 PubMed ID: 39047051
Summary: Despite the deep conservation of the DNA damage response (DDR) pathway, cells in different contexts vary widely in their susceptibility to DNA damage and their propensity to undergo apoptosis as a result of genomic lesions. One of the cell signaling pathways implicated in modulating the DDR is the highly conserved Wnt pathway, which is known to promote resistance to DNA damage caused by ionizing radiation in a variety of human cancers. However, the mechanisms linking Wnt signal transduction to the DDR remain unclear. Heuse a genetically encoded system in Drosophila to reliably induce consistent levels of DNA damage in vivo, and demonstrate that canonical Wnt signaling in the wing imaginal disc buffers cells against apoptosis in the face of DNA double-strand breaks. Wg, the primary Wnt ligand in Drosophila, activates epidermal growth factor receptor (EGFR) signaling via the ligand-processing protease Rhomboid, which, in turn, modulates the DDR in a Chk2<.a>-, p53-, and E2F1-dependent manner. These studies provide mechanistic insight into the modulation of the DDR by the Wnt and EGFR pathways in vivo in a highly proliferative tissue. Furthermore, they reveal how the growth and patterning functions of Wnt signaling are coupled with prosurvival, antiapoptotic activities, thereby facilitating developmental robustness in the face of genomic damage. |
| Turley, J., Robertson, F., Chenchiah, I. V., Liverpool, T. B., Weavers, H., Martin, P. (2024). AI reveals a damage signalling hierarchy that coordinates different cell behaviours driving wound re-epithelialisation. Development, PubMed ID: 39177163
Summary: One of the key tissue movements driving closure of a wound is re-epithelialisation. Earlier wound healing studies have described the dynamic cell behaviours that contribute to wound re-epithelialisation, including cell division, cell shape changes and cell migration, as well as the signals that might regulate these cell behaviours. This study used a series of deep learning tools to quantify the contributions of each of these cell behaviours from movies of repairing wounds in the Drosophila pupal wing epithelium. Tests were performed to show how each is altered following knockdown of the conserved wound repair signals, Ca2+ and JNK, as well as ablation of macrophages which supply growth factor signals believed to orchestrate aspects of the repair process. These genetic perturbation experiments provide quantifiable insights regarding how these wound signals impact cell behaviours. This study found that Ca2+ signalling is a master regulator required for all contributing cell behaviours; JNK signalling primarily drives cell shape changes and divisions, whereas signals from macrophages regulate largely cell migration and proliferation. These studies show AI to be a valuable tool for unravelling complex signalling hierarchies underlying tissue repair. | Al Asafen, H., Beseli, A., Chen, H. Y., Hiremath, S., Williams, C. M., Reeves, G. T. (2024). Dynamics of BMP signaling and stable gene expression in the early Drosophila embryo. Biol Open, 13(9) PubMed ID: 39207258
Summary: In developing tissues, morphogen gradients are thought to initialize gene expression patterns. However, the relationship between the dynamics of morphogen-encoded signals and gene expression decisions is largely unknown. This study examined the dynamics of the Bone Morphogenetic Protein (BMP) pathway in Drosophila blastoderm-stage embryos. In this tissue, the BMP pathway is highly dynamic: it begins as a broad and weak signal on the dorsal half of the embryo, then 20-30 min later refines into a narrow, intense peak centered on the dorsal midline. This dynamical progression of the BMP signal raises questions of how it stably activates target genes. Therefore, live imaging of the BMP signal was performed; dorsal-lateral cells were found to experience only a short transient in BMP signaling, after which the signal is lost completely. Moreover, the transcriptional response of the BMP target gene pannier was measured in live embryos, and it was found to remain activated in dorsal-lateral cells, even after the BMP signal is lost. These findings may suggest that the BMP pathway activates a memory, or 'ratchet' mechanism that may sustain gene expression. |
| Nourisanami, F., Sobol, M., Li, Z., Horvath, M., Kowalska, K., Kumar, A., Vlasak, J., Koupilova, N., Luginbuhl, D. J., Luo, L., Rozbesky, D. (2024). Molecular mechanisms of proteoglycan-mediated semaphorin signaling in axon guidance. Proc Natl Acad Sci U S A, 121(31):e2402755121 PubMed ID: 39042673
Summary: The precise assembly of a functional nervous system relies on axon guidance cues. Beyond engaging their cognate receptors and initiating signaling cascades that modulate cytoskeletal dynamics, guidance cues also bind components of the extracellular matrix, notably proteoglycans, yet the role and mechanisms of these interactions remain poorly understood. This study found that Drosophila secreted semaphorins bind specifically to glycosaminoglycan (GAG) chains of proteoglycans, showing a preference based on the degree of sulfation. Structural analysis of Sema2b unveiled multiple GAG-binding sites positioned outside canonical plexin-binding site, with the highest affinity binding site located at the C-terminal tail, characterized by a lysine-rich helical arrangement that appears to be conserved across secreted semaphorins. In vivo studies revealed a crucial role of the Sema2b C-terminal tail in specifying the trajectory of olfactory receptor neurons. It is proposed that secreted semaphorins tether to the cell surface through interactions with GAG chains of proteoglycans, facilitating their presentation to cognate receptors on passing axons. | Guo, P., Li, B., Dong, W., Zhou, H., Wang, L., Su, T., Carl, C., Zheng, Y., Hong, Y., Deng, H., Pan, D. (2024). PI4P-mediated solid-like Merlin condensates orchestrate Hippo pathway regulation. Science, 385(6709):eadf4478 PubMed ID: 39116228
Summary: Despite recent studies implicating liquid-like biomolecular condensates in diverse cellular processes, many biomolecular condensates exist in a solid-like state, and their function and regulation are less understood. This study shows that the tumor suppressor Merlin, an upstream regulator of the Hippo pathway, localizes to both cell junctions and medial apical cortex in Drosophila epithelia, with the latter forming solid-like condensates that activate Hippo signaling. Merlin condensation required phosphatidylinositol-4-phosphate (PI4P)-mediated plasma membrane targeting and was antagonistically controlled by Pez and cytoskeletal tension through plasma membrane PI4P regulation. The solid-like material properties of Merlin condensates are essential for physiological function and protect the condensates against external perturbations. Collectively, these findings uncover an essential role for solid-like condensates in normal physiology and reveal regulatory mechanisms for their formation and disassembly. |
Monday June 23rd - Cell Cycle |
| Leca, N., Barbosa, F., Rodriguez-Calado, S., Moura, M., Pedroso, P. D., Pinto, I., Verza, A. E., Bange, T., Sunkel, C. E., Barisic, M., Maresca, T. J., Conde, C. (2024). Proximity-based activation of AURORA A by MPS1 potentiates error correction. bioRxiv, PubMed ID: 38948877
Summary: Faithfull 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 cross-talk that is required for efficient error correction, showcasing the ability of kinetochores to modulate centrosome outputs to ensure proper chromosome segregation. | Haseeb, M. A., Weng, K. A., Bickel, S. E. (2024). Chromatin-associated cohesin turns over extensively and forms new cohesive linkages in Drosophila oocytes during meiotic prophase. Curr Biol, 34(13):2868-2879. PubMed ID: 38870933
Summary: In dividing cells, accurate chromosome segregation depends on sister chromatid cohesion, protein linkages that are established during DNA replication. Faithful chromosome segregation in oocytes requires that cohesion, first established in S phase, remain intact for days to decades, depending on the organism. Premature loss of meiotic cohesion in oocytes leads to the production of aneuploid gametes and contributes to the increased incidence of meiotic segregation errors as women age (maternal age effect). The prevailing model is that cohesive linkages do not turn over in mammalian oocytes. However, it has been previously reported that cohesion-related defects arise in Drosophila oocytes when individual cohesin subunits or cohesin regulators are knocked down after meiotic S phase. This study used two strategies to express a tagged cohesin subunit exclusively during mid-prophase in Drosophila oocytes; newly expressed cohesin was found to be used used to form de novo linkages after meiotic S phase. Cohesin along the arms of oocyte chromosomes appears to completely turn over within a 2-day window during prophase, whereas replacement is less extensive at centromeres. Unlike S-phase cohesion establishment, the formation of new cohesive linkages during meiotic prophase does not require acetylation of conserved lysines within the Smc head. These findings indicate that maintenance of cohesion between S phase and chromosome segregation in Drosophila oocytes requires an active cohesion rejuvenation program that generates new cohesive linkages during meiotic prophase. |
| Shapiro, J. G., Changela, N., Jang, J. K., Joshi, J. N., McKim, K. S. (2024). Distinct checkpoint and homolog biorientation pathways regulate meiosis I in Drosophila oocytes. bioRxiv, PubMed ID: 39229242
Summary: Mitosis and meiosis have two mechanisms for regulating the accuracy of chromosome segregation: error correction and the spindle assembly checkpoint (SAC). This study investigated the function of several checkpoint proteins in meiosis I of Drosophila oocytes. Evidence of a SAC response by several of these proteins is found upon depolymerization of microtubules by colchicine. However, unattached kinetochores or errors in biorientation of homologous chromosomes does not induce a SAC response. Furthermore, the metaphase I arrest does not depend on SAC genes, suggesting the APC is inhibited even if the SAC is silenced. Two SAC proteins, ROD of the ROD-ZW10-Zwilch (RZZ) complex and MPS1, are also required for the biorientation of homologous chromosomes during meiosis I, suggesting an error correction function. Both proteins aid in preventing or correcting erroneous attachments and depend on SPC105R for localization to the kinetochore. This study has defined a region of SPC105R, amino acids 123-473, that is required for ROD localization and biorientation of homologous chromosomes at meiosis I. Surprisingly, ROD removal, or "streaming", is independent of the dynein adaptor Spindly and is not linked to the stabilization of end-on attachments. Instead, meiotic RZZ streaming appears to depend on cell cycle stage and may be regulated independently of kinetochore attachment or biorientation status. Dynein adaptor Spindly is also required for biorientation at meiosis I, and surprisingly, the direction of RZZ streaming. | Joshi, J. N., Changela, N., Mahal, L., Jang, J., Defosse, T., Wang, L. I., Das, A., Shapiro, J. G., McKim, K. (2024). Meiosis-specific functions of kinetochore protein SPC105R required for chromosome segregation in Drosophila oocytes. Mol Biol Cell, 35(8):ar105 PubMed ID: 38865189
Summary: The reductional division of meiosis I requires the separation of chromosome pairs towards opposite poles. The outer kinetochore protein SPC105R/KNL1 has been implemented in driving meiosis I chromosome segregation through lateral attachments to microtubules and coorientation of sister centromeres. To identify the domains of SPC105R that are critical for meiotic chromosome segregation, an RNAi-resistant gene expression system was developed. The SPC105R C-terminal domain (aa 1284-1960) was shown to be is necessary and sufficient for recruiting NDC80 to the kinetochore and building the outer kinetochore. Furthermore, the C-terminal domain recruits BUBR1, which in turn recruits the cohesion protection proteins MEI-S332 and PP2A. Of the remaining 1283 amino acids, the first 473 are most important for meiosis. The first 123 amino acids of the N-terminal half of SPC105R contain the conserved SLRK and RISF motifs that are targets of PP1 and Aurora B kinase and are most important for regulating the stability of microtubule attachments and maintaining metaphase I arrest. The region between amino acids 124 and 473 are required for lateral microtubule attachments and biorientation of homologues, which are critical for accurate chromosome segregation in meiosis I. |
| Lake, C. M., Gardner, J., Briggs, S., Yu, Z., McKown, G., Hawley, R. S. (2024). The deubiquitinase Usp7 in Drosophila melanogaster is required for synaptonemal complex maintenance. Proc Natl Acad Sci U S A, 121(36):e2409346121 PubMed ID: 39190345
Summary: Meiosis is a form of cell division that is essential to sexually reproducing organisms and is therefore highly regulated. Each event of meiosis must occur at the correct developmental stage to ensure that chromosomes are segregated properly during both meiotic divisions. One unique meiosis-specific structure that is tightly regulated in terms of timing of assembly and disassembly is the synaptonemal complex (SC). While the mechanism(s) for assembly and disassembly of the SC are poorly understood in Drosophila melanogaster, posttranslational modifications, including ubiquitination and phosphorylation, are known to play a role. This study identified a role for the deubiquitinase Usp7 in the maintenance of the SC in early prophase and showed that its function in SC maintenance is independent of the meiotic recombination process. Using two usp7 shRNA constructs that result in different knockdown levels, the presence of SC through early/mid-pachytene was shown to be critical for normal levels and placement of crossovers. | Zhang, Q., Wang, Y., Bu, Z., Zhang, Y., Zhang, Q., Li, L., Yan, L., Wang, Y., Zhao, S. (2024). Ras promotes germline stem cell division in Drosophila ovaries. Stem cell reports, 19(8):1205-1216 PubMed ID: 39029459
Summary: The Ras family genes are proto-oncogenes that are highly conserved from Drosophila to humans. In Drosophila, Ras(V12) is a constitutively activated form of the Ras oncoprotein, and its function in cell-cycle progression is context dependent. However, how it influences the cell cycle of female germline stem cells (GSCs) still remains unknown. Using both wild-type GSCs and bam mutant GSC-like cells as model systems, this study determined that Ras(V12) overexpression promotes GSC division, not growth, opposite to that in somatic wing disc cells. Ras performs this function through activating the mitogen-activated protein kinase (MAPK) signaling. This signaling is activated specifically in the M phase of mitotic germ cells, including both wild-type GSCs and bam mutant GSC-like cells. Furthermore, Ras(V12) overexpression triggers polyploid nurse cells to die through inducing mitotic stress. Given the similarities between Drosophila and mammalian GSCs, it is proposed that the Ras/MAPK signaling also promotes mammalian GSC division. |
Thursday, June 19th - Behavior |
| Kubrak, O., Jorgensen, A. F., Koyama, T., Lassen, M., Nagy, S., Hald, J., Mazzoni, G., Madsen, D., Hansen, J. B., Larsen, M. R., Texada, M. J., Hansen, J. L., Halberg, K. V., Rewitz, K. (2024). LGR signaling mediates muscle-adipose tissue crosstalk and protects against diet-induced insulin resistance. Nat Commun, 15(1):6126 PubMed ID: 39033139
Summary: Obesity impairs tissue insulin sensitivity and signaling, promoting type-2 diabetes. Although improving insulin signaling is key to reversing diabetes, the multi-organ mechanisms regulating this process are poorly defined. This study screen the secretome and receptome in Drosophila to identify the hormonal crosstalk affecting diet-induced insulin resistance and obesity. This study discovered a complex interplay between muscle, neuronal, and adipose tissues, mediated by Bone Morphogenetic Protein (BMP) signaling and the hormone Bursicon, that enhances insulin signaling and sugar tolerance. Muscle-derived BMP signaling, induced by sugar, governs neuronal Bursicon signaling. Bursicon, through its receptor Rickets, a Leucine-rich-repeat-containing G-protein coupled receptor (LGR), improves insulin secretion and insulin sensitivity in adipose tissue, mitigating hyperglycemia. In mouse adipocytes, loss of the Rickets ortholog LGR4 blunts insulin responses, showing an essential role of LGR4 in adipocyte insulin sensitivity.These findings reveal a muscle-neuronal-fat-tissue axis driving metabolic adaptation to high-sugar conditions, identifying LGR4 as a critical mediator in this regulatory network. | Stupski, S. D., van Breugel, F. (2024). Wind gates olfaction-driven search states in free flight. Curr Biol, PubMed ID: 39067453
Summary: For organisms tracking a chemical cue to its source, the motion of their surrounding fluid provides crucial information for success. Swimming and flying animals engaged in olfaction-driven search often start by turning into the direction of an oncoming wind or water current. However, it is unclear how organisms adjust their strategies when directional cues are absent or unreliable, as is often the case in nature. This study used the genetic toolkit of Drosophila melanogaster to develop an optogenetic paradigm to deliver temporally precise "virtual" olfactory experiences for free-flying animals in either laminar wind or still air. It was first confirmed that in laminar wind flies turn upwind. Furthermore, it was shown that they achieve this using a rapid (~100 ms) turn, implying that flies estimate the ambient wind direction prior to "surging" upwind. In still air, flies adopt a remarkably stereotyped "sink and circle" search state characterized by ~60° turns at 3-4 Hz, biased in a consistent direction. Together, these results show that Drosophila melanogaster assesses the presence and direction of ambient wind prior to deploying a distinct search strategy. In both laminar wind and still air, immediately after odor onset, flies decelerate and often perform a rapid turn. Both maneuvers are consistent with predictions from recent control theoretic analyses for how insects may estimate properties of wind while in flight. It is suggested that flies may use their deceleration and "anemometric" turn as active sensing maneuvers to rapidly gauge properties of their wind environment before initiating a proximal or upwind search routine. |
| Booth, J. H., Meek, A. T., Kronenberg, N. M., Pulver, S. R., Gather, M. C. (2024). Optical mapping of ground reaction force dynamics in freely behaving Drosophila melanogaste larvaer. Elife, 12 PubMed ID: 39042447
Summary: During locomotion, soft-bodied terrestrial animals solve complex control problems at substrate interfaces, but understanding of how they achieve this without rigid components remains incomplete. This study developed new all-optical methods based on optical interference in a deformable substrate to measure ground reaction forces (GRFs) with micrometre and nanonewton precision in behaving Drosophila larvae. Combining this with a kinematic analysis of substrate-interfacing features, new light is shed onto the biomechanical control of larval locomotion. Crawling in larvae measuring ~1 mm in length involves an intricate pattern of cuticle sequestration and planting, producing GRFs of 1-7 μN. Larvae insert and expand denticulated, feet-like structures into substrates as they move, a process not previously observed in soft-bodied animals. These 'protopodia' form dynamic anchors to compensate counteracting forces. This work provides a framework for future biomechanics research in soft-bodied animals and promises to inspire improved soft-robot design. | Poissonnier, L. A., Danchin, E., Isabel, G. (2024). Male attractiveness is subjective to exposure to males of different attractiveness in fruit flies. Sci Rep, 14(1):16463 PubMed ID: 39014083
Summary: Mate choice is a crucial decision in any animal. In terms of fitness, the best mate is the one that leads to the most abundant and productive offspring. Pairing with a low-quality mate would reduce fitness, generating selection for accurate and subtle mate choice in all animal species. Hence, mate choice is expected to be highly context dependent, and should depend on other potential options. For instance, a medium-quality male can constitute the best option when all other males are in poorer condition, but not when there are better-quality males available. Therefore, animals are predicted to gather information about their social context and adapt their mate choice to it. This study reports on experiments in which the social environment of females of Drosophila melanogaster were manipulated; after encountering a high or a low-quality male, females take more or less time to accept copulation with another male, suggesting that females adapt their mating strategy to their social context. This study also reports on a similar effect in D. biarmiceps. Thus, male attractiveness appears to depend on the quality of recently met males, suggesting that male attractiveness is subjective, indicating plastic and context dependent mate choice. |
| Lynn, K., Ichinose, T., Tanimoto, H. (2024). Peer-induced quiescence of male Drosophila melanogaster following copulation.. Front Behav Neurosci, 18:1414029 PubMed ID: 39081685
Summary: Mating experience impacts the physiology and behavior of animals. Although mating effects of female Drosophila melanogaster have been studied extensively, the behavioral changes of males following copulation have not been fully understood. This study characterized the mating-dependent behavioral changes of male flies, especially focusing on fly-to-fly interaction, and their dependence on rearing conditions. The data demonstrate that male flies quiesce their courtship toward both females and males, as well as their locomotor activity. This post-copulatory quiescence appears to be contingent upon the presence of a peer, as minimal variation is noted in locomotion when the male is measured in isolation. Interestingly, copulated males influence a paired male without successful copulation to reduce his locomotion. These findings point to a conditional behavioral quiescence following copulation, influenced by the presence of other flies. | Otarola-Jimenez, J., Nataraj, N., Bisch-Knaden, S., Hansson, B. S., Knaden, M. (2024). Oviposition experience affects oviposition preference in Drosophila melanogaster. iScience, 27(8):110472 PubMed ID: 39129830
Summary: Learning, memorizing, and recalling of potential ovipositing sites can influence oviposition preference. Classical conditioning experiments have shown that vinegar flies can learn the association of olfactory, gustatory, or visual stimuli with either positive or negative unconditioned stimuli. However, less is known about whether similar associations are formed in an ecologically more relevant context like during oviposition. The current experiments reveal that Drosophila melanogaster females increase their preference for substrates they have already experienced. However, this change of preference requires that the flies not only smelled or touched the substrates but also oviposited on them. It was furthermore shown that such an experience results in long-term memory lasting for at least 4 days, i.e., a duration that so far was shown only for aversive conditioning. This study thus reveals a different form of associative learning in D. melanogaster that might be highly relevant for settling novel ecological niches. |
Wednescay, June 18th - Disease Models |
| Yadav, S., Graham, A., Al Hammood, F., Garbark, C., Vasudevan, D., Pandey, U., Asara, J. M., Rajasundaram, D., Parkhitko, A. A. (2024). Unique tau- and synuclein-dependent metabolic reprogramming in neurons distinct from normal aging. Aging Cell:e14277 PubMed ID: 39137949
Summary: Neuronal cells are highly specialized cells and have a specific metabolic profile to support their function. It has been demonstrated that the metabolic profiles of different cells/tissues undergo significant reprogramming with advancing age, which has often been considered a contributing factor towards aging-related diseases including Alzheimer's (AD) and Parkinson's (PD) diseases. However, it is unclear if the metabolic changes associated with normal aging predispose neurons to disease conditions or a distinct set of metabolic alterations happen in neurons in AD or PD which might contribute to disease pathologies. To decipher the changes in neuronal metabolism with age, in AD, or in PD, high-throughput steady-state metabolite profiling was performed on heads in wildtype Drosophila and in Drosophila models relevant to AD and PD. Intriguingly, it was found that the spectrum of affected metabolic pathways is dramatically different between normal aging, Tau, or Synuclein overexpressing neurons. Genetic targeting of the purine and glutamate metabolism pathways, which were dysregulated in both old age and disease conditions partially rescued the neurodegenerative phenotype associated with the overexpression of wildtype and mutant tau. These findings support a "two-hit model" to explain the pathological manifestations associated with AD where both aging- and Tau/Synuclein- driven metabolic reprogramming events cooperate with each other, and targeting both could be a potent therapeutic strategy. | Ruchitha, B. G., Kumar, N., Sura, C., Tung, S. (2024). Selection for greater dispersal in early life leads to faster age-dependent decline in locomotor activity and shorter lifespan. J Evol Biol, PubMed ID: 39105302
Summary: Locomotor activity is one of the major traits that is affected by age. Greater locomotor activity is also known to evolve in the course of dispersal evolution. However, the impact of dispersal evolution on the functional senescence of locomotor activity is largely unknown. This knowledge gap using large outbred populations of Drosophila melanogaster selected for increased dispersal. Locomotor activity of these flies was assessed at regular intervals until a late age. Longevity of these flies was also recorded. Locomotor activity was shown to decline with age in general. However interestingly, activity level of dispersal selected populations never drops below the ancestry-matched-controls, despite the rate of age-dependent decline in activity of the dispersal selected populations being greater than their respective controls. Dispersal selected population was also found to have shorter lifespan as compared to its control, a potential cost of elevated level of activity throughout their life. These results are crucial in the context of invasion biology as contemporary climate change, habitat degradation, and destruction provide congenial conditions for dispersal evolution. Such controlled and tractable studies investigating the ageing pattern of important functional traits are important in the field of biogerontology as well. |
| Lim, J. J., Noh, S., Kang, W., Hyun, B., Lee, B. H., Hyun, S. (2024). Pharmacological inhibition of USP14 delays proteostasis-associated aging in a proteasome-dependent but foxo-independent manner. Autophagy:1-17 PubMed ID: 39113571
Summary: Aging is often accompanied by a decline in proteostasis, manifested as an increased propensity for misfolded protein aggregates, which are prevented by protein quality control systems, such as the ubiquitin-proteasome system (UPS) and macroautophagy/autophagy. Although the role of the UPS and autophagy in slowing age-induced proteostasis decline has been elucidated, limited information is available on how these pathways can be activated in a collaborative manner to delay proteostasis-associated aging. This study showed that activation of the UPS via the pharmacological inhibition of USP14 (ubiquitin specific peptidase 14) using IU1 improves proteostasis and autophagy decline caused by aging or proteostatic stress in Drosophila and human cells. Treatment with IU1 not only alleviated the aggregation of polyubiquitinated proteins in Drosophila flight muscles but also extended the fly lifespan with enhanced locomotive activity via simultaneous activation of the UPS and autophagy. Interestingly, the effect of this drug disappeared when proteasomal activity was inhibited, but was evident upon proteostasis disruption by foxo mutation. Overall, these findings shed light on potential strategies to efficiently ameliorate age-associated pathologies associated with perturbed proteostasis. | Dondi, C., Vogler, G., Gupta, A., Walls, S. M., Kervadec, A., Marchant, J., Romero, M. R., Diop, S., Goode, J., Thomas, J. B., Colas, A. R., Bodmer, R., Montminy, M., Ocorr, K. (2024). The nutrient sensor CRTC and Sarcalumenin/thinman represent an alternate pathway in cardiac hypertrophy. Cell Rep, 43(8):114549 PubMed ID: 39093699
Summary: CREB-regulated transcription co-activator (CRTC) is activated by Calcineurin (CaN) to regulate gluconeogenic genes. CaN also has roles in cardiac hypertrophy. This study explored a cardiac-autonomous role for CRTC in cardiac hypertrophy. In Drosophila, CRTC mutants exhibit severe cardiac restriction, myofibrillar disorganization, fibrosis, and tachycardia. Cardiac-specific CRTC knockdown (KD) phenocopies mutants, and cardiac overexpression causes hypertrophy. CaN-induced hypertrophy in Drosophila is reduced in CRTC mutants, suggesting that CRTC mediates the effects. RNA sequencing (RNA-seq) of CRTC-KD and overexpressing hearts reveals contraregulation of metabolic genes. Genes with conserved CREB sites include the fly ortholog of Sarcalumenin, a Ca(2+)-binding protein. Cardiac manipulation of this gene recapitulates the CRTC-KD and -overexpression phenotypes. CRTC KD in zebrafish also causes cardiac restriction, and CRTC KD in human induced cardiomyocytes causes a reduction in Srl expression and increased action potential duration. These data from three model systems suggest that CaN-CRTC-Sarcalumenin signaling represents an alternate, conserved pathway underlying cardiac function and hypertrophy. |
| Vannelli, A., Mariano, V., Bagni, C., Kanellopoulos, A. K. (2024). Activation of the 5-HT1A Receptor by Eltoprazine Restores Mitochondrial and Motor Deficits in a Drosophila Model of Fragile X Syndrome. Int J Mol Sci, 25(16) PubMed ID: 39201473
Summary: Neurons rely on mitochondrial energy metabolism for essential functions like neurogenesis, neurotransmission, and synaptic plasticity. Mitochondrial dysfunctions are associated with neurodevelopmental disorders including Fragile X syndrome (FXS), the most common cause of inherited intellectual disability, which also presents with motor skill deficits. However, the precise role of mitochondria in the pathophysiology of FXS remains largely unknown. Notably, previous studies have linked the serotonergic system and mitochondrial activity to FXS. This study investigates the potential therapeutic role of serotonin receptor 1A (5-HT1A) in FXS. Using the Drosophila model of FXS, it was demonstrated that treatment with eltoprazine, a 5-HT1A agonist, can ameliorate synaptic transmission, correct mitochondrial deficits, and ultimately improve motor behavior. While these findings suggest that the 5-HT1A-mitochondrial axis may be a promising therapeutic target, further investigation is needed in the context of FXS. | Wei, F., Liu, S., Liu, J., Sun, Y., Allen, A. E., Reid, M. A., Locasale, J. W. (2024). Separation of reproductive decline from lifespan extension during methionine restriction. Nature aging, 4(8):1089-1101 PubMed ID: 39060538
Summary: Lifespan-extending interventions are generally thought to result in reduced fecundity. The generality of this principle and how it may extend to nutrition and metabolism is not understood. This study considered dietary methionine restriction (MR), a lifespan-extending intervention linked to Mediterranean and plant-based diets. Using a chemically defined diet that was developed for Drosophila melanogaster, this study surveyed the nutritional landscape in the background of MR and found that folic acid, a vitamin linked to one-carbon metabolism, notably was the lone nutrient that restored reproductive capacity while maintaining lifespan extension. In vivo isotope tracing, metabolomics and flux analysis identified the tricarboxylic cycle and redox coupling as major determinants of the MR-folic acid benefits, in part, as they related to sperm function. Together these findings suggest that dietary interventions optimized for longevity may be separable from adverse effects such as reproductive decline. |
Tuesday, June 17th - Adult Neural Development, Structure and Function |
| Koch, S., Kandimalla, P., Padilla, E., Kaur, S., Kaur, R., Nguyen, M., Nelson, A., Khalsa, S., Younossi-Hartenstein, A., Hartenstein, V. (2024). Structural changes shaping the Drosophila ellipsoid body ER-neurons during development and aging. Dev Biol, 516:96-113 PubMed ID: 39089472
Summary: The ellipsoid body (EB) of the insect brain performs pivotal functions in controlling navigation. Input and output of the EB is provided by multiple classes of R-neurons (now referred to as ER-neurons) and columnar neurons which interact with each other in a stereotypical and spatially highly ordered manner. The developmental mechanisms that control the connectivity and topography of EB neurons are largely unknown. One indispensable prerequisite to unravel these mechanisms is to document in detail the sequence of events that shape EB neurons during their development. This study analyzed the development of the Drosophila EB. In addition to globally following the ER-neuron and columnar neuron (sub)classes in the spatial context of their changing environment a single cell analysis was performed using the multi-color flip out (MCFO) system to analyze the developmental trajectory of ER-neurons at different pupal stages, young adults (4d) and aged adults (∼60d). The EB was shown to develop as a merger of two distinct elements, a posterior and anterior EB primordium (prEBp and prEBa, respectively. ER-neurons belonging to different subclasses form growth cones and filopodia that associate with the prEBp and prEBa in a pattern that, from early pupal stages onward, foreshadows their mature structure. Filopodia of all ER-subclasses are initially much longer than the dendritic and terminal axonal branches they give rise to, and are pruned back during late pupal stages. Interestingly, extraneous branches, particularly significant in the dendritic domain, are a hallmark of ER-neuron structure in aged brains. Aging is also associated with a decline in synaptic connectivity from columnar neurons, as well as upregulation of presynaptic protein (Brp) in ER-neurons. These findings advance the EB (and ER-neurons) as a favorable system to visualize and quantify the development and age-related decline of a complex neuronal circuitry. | Someya, W., Akutsu, T., Nacher, J. C. (2024). Target control of linear directed networks based on the path cover problem. Sci Rep, 14(1):16881 PubMed ID: 39043768
Summary: Securing complete control of complex systems comprised of tens of thousands of interconnected nodes holds immense significance across various fields, spanning from cell biology and brain science to human-engineered systems. However, depending on specific functional requirements, it can be more practical and efficient to focus on a pre-defined subset of nodes for control, a concept known as target control. While some methods have been proposed to find the smallest driver node set for target control, they either rely on heuristic approaches based on k-walk theory, lacking a guarantee of optimal solutions, or they are overly complex and challenging to implement in real-world networks. To address this challenge, this study introduced a simple and elegant algorithm, inspired by the path cover problem, which efficiently identifies the nodes required to control a target node set within polynomial time. To practically apply the algorithm in real-world systems, several networks were selected, in which a specific set of nodes with functional significance can be designated as a target control set. The analysed systems include the complete connectome of the nematode worm C. elegans, the recently disclosed connectome of the Drosophila larval brain, as well as dozens of genome-wide metabolic networks spanning major plant lineages. The target control analysis shed light on distinctions between neural systems in nematode worms and larval brain insects, particularly concerning the number of nodes necessary to regulate specific functional systems. Furthermore, this analysis uncovers evolutionary trends within plant lineages, notably when examining the proportion of nodes required to control functional pathways. |
| Liu, J., Wang, Y., Liu, X., Han, J., Tian, Y. (2024). Spatiotemporal changes in Netrin/Dscam1 signaling dictate axonal projection direction in Drosophila small ventral lateral clock neurons. Elife, 13 PubMed ID: 39052321
Summary: Axon projection is a spatial- and temporal-specific process in which the growth cone receives environmental signals guiding axons to their final destination. However, the mechanisms underlying changes in axonal projection direction without well-defined landmarks remain elusive. This study presents evidence showcasing the dynamic nature of axonal projections in Drosophila's small ventral lateral clock neurons (s-LNvs). The findings reveal that these axons undergo an initial vertical projection in the early larval stage, followed by a subsequent transition to a horizontal projection in the early-to-mid third instar larvae. The vertical projection of s-LNv axons correlates with mushroom body calyx expansion, while the s-LNv-expressed Down syndrome cell adhesion molecule (Dscam1) interacts with Netrins to regulate the horizontal projection. During a specific temporal window, locally newborn dorsal clock neurons secrete Netrins, facilitating the transition of axonal projection direction in s-LNvs. This study establishes a compelling in vivo model to probe the mechanisms of axonal projection direction switching in the absence of clear landmarks. These findings underscore the significance of dynamic local microenvironments in the complementary regulation of axonal projection direction transitions. | Sharma, P. N., Sheeba, V. (2024). Reorganization of circadian activity and the pacemaker circuit under novel light regimes. Proceedings Biological sciences, 291(2027):20241190 PubMed ID: 39043245
Summary: Many environmental features are cyclic, with predictable changes across the day, seasons and latitudes. Additionally, anthropogenic, artificial-light-induced changes in photoperiod or shiftwork-driven novel light/dark cycles also occur. Endogenous timekeepers or circadian clocks help organisms cope with such changes. The remarkable plasticity of clocks is evident in the waveforms of behavioural and molecular rhythms they govern. Despite detailed mechanistic insights into the functioning of the circadian clock, practical means to manipulate activity waveform are lacking. Previous studies using a nocturnal rodent model showed that novel light regimes caused locomotor activity to bifurcate such that mice showed two bouts of activity restricted to the dimly lit phases. This study explored the generalizability of these findings and leveraged the genetic toolkit of Drosophila melanogaster to obtain mechanistic insights into this unique phenomenon. Dim scotopic illumination of specific durations induces circadian photoreceptor CRYPTOCHROME-dependent activity bifurcation in male flies. Circadian reorganization was shown of the pacemaker circuit, wherein the 'evening' neurons regulate the timing of both bouts of activity under novel light regimes. These findings indicate that such environmental regimes can be exploited to design light cycles, which can ease the circadian waveform into synchronizing with challenging conditions. |
| Neitz, A. F., Carter, B. M., Ceriani, M. F., Ellisman, M. H., de la Iglesia, H. O. (2024). Suprachiasmatic nucleus VIPergic fibers show a circadian rhythm of expansion and retraction. Curr Biol, PubMed ID: 39127047
Summary: In animals, overt circadian rhythms of physiology and behavior are centrally regulated by a circadian clock located in specific brain regions. In the fruit fly Drosophila and in mammals, these clocks rely on single-cell oscillators, but critical for their function as central circadian pacemakers are network properties that change dynamically throughout the circadian cycle as well as in response to environmental stimuli. In the fly, this plasticity involves circadian rhythms of expansion and retraction of clock neuron fibers. Whether these drastic structural changes are a universal property of central neuronal pacemakers is unknown. To address this question, neurons of the mouse suprachiasmatic nucleus (SCN) were studied that express vasoactive intestinal polypeptide (VIP), which are critical for the SCN to function as a central circadian pacemaker. By targeting the expression of the fluorescent protein tdTomato to these neurons and using tissue clearing techniques to visualize all SCN VIPergic neurons and their fibers, this study showed that, similar to clock neurons in the fly, VIPergic fibers undergo a daily rhythm of expansion and retraction, with maximal branching during the day. This rhythm is circadian, as it persists under constant environmental conditions and is present in both males and females. It is proposed that circadian structural remodeling of clock neurons represents a key feature of central circadian pacemakers that is likely critical to regulate network properties, the response to environmental stimuli, and the regulation of circadian outputs. | Guillemin, J., Li, J., Li, V., McDowell, S. A. T., Audette, K., Davis, G., Jelen, M., Slamani, S., Kelliher, L., Gordon, M. D., Stanley, M. (2024). Taste cells expressing Ionotropic Receptor 94e reciprocally impact feeding and egg laying in Drosophila.. Cell Rep, 43(8):114625 PubMed ID: 39141516
Summary: Chemosensory cells across the body of Drosophila melanogaster evaluate the environment to prioritize certain behaviors. Previous mapping of gustatory receptor neurons (GRNs) on the fly labellum identified a set of neurons in L-type sensilla that express Ionotropic Receptor 94e (IR94e), but the impact of IR94e GRNs on behavior remains unclear. This study used optogenetics and chemogenetics to activate IR94e neurons and found that they drive mild feeding suppression but enhance egg laying. In vivo calcium imaging revealed that IR94e GRNs respond strongly to certain amino acids, including glutamate, and that IR94e plus co-receptors IR25a and IR76b are required for amino acid detection. Furthermore, IR94e mutants show behavioral changes to solutions containing amino acids, including increased consumption and decreased egg laying. Overall, these results suggest that IR94e GRNs on the fly labellum discourage feeding and encourage egg laying as part of an important behavioral switch in response to certain chemical cues. |
Thursday, June 12th - Genes, Enzymes, and Proteins |
| Khodaverdian, V., Sano, T., Maggs, L. R., Tomarchio, G., Dias, A., Tran, M., Clairmont, C., McVey, M. (2024). REV1 coordinates a multi-faceted tolerance response to DNA alkylation damage and prevents chromosome shattering in Drosophila melanogaster. PLoS Genet, 20(7):e1011181 PubMed ID: 39074150
Summary: When replication forks encounter damaged DNA, cells utilize damage tolerance mechanisms to allow replication to proceed. These include translesion synthesis at the fork, postreplication gap filling, and template switching via fork reversal or homologous recombination. The extent to which these different damage tolerance mechanisms are utilized depends on cell, tissue, and developmental context-specific cues, the last two of which are poorly understood. To address this gap, damage tolerance responses were investigated in Drosophila melanogaster. Tolerance of DNA alkylation damage in rapidly dividing larval tissues depends heavily on translesion synthesis. Furthermore, it was shown that the REV1 protein plays a multi-faceted role in damage tolerance in Drosophila. Larvae lacking REV1 are hypersensitive to methyl methanesulfonate (MMS) and have highly elevated levels of γ-H2Av (Drosophila γ-H2AX) foci and chromosome aberrations in MMS-treated tissues. Loss of the REV1 C-terminal domain (CTD), which recruits multiple translesion polymerases to damage sites, sensitizes flies to MMS. In the absence of the REV1 CTD, DNA polymerase eta and DNA polymerase zeta become critical for MMS tolerance. In addition, flies lacking REV3, the catalytic subunit of polymerase zeta, require the deoxycytidyl transferase activity of REV1 to tolerate MMS. Together, the results demonstrate that Drosophila prioritize the use of multiple translesion polymerases to tolerate alkylation damage and highlight the critical role of REV1 in the coordination of this response to prevent genome instability. | Klemm, J., Van Hazel, C., Harris, R. (2024). Regeneration following tissue necrosis is mediated by non-apoptotic caspase activity. bioRxiv, PubMed ID: 39091851
Summary: Tissue necrosis is a devastating complication for many human diseases and injuries. Unfortunately, understanding of necrosis and how it impacts surrounding healthy tissue - an essential consideration when developing methods to treat such injuries - has been limited by a lack of robust genetically tractable models. Previous work established a method to study necrosis-induced regeneration in the Drosophila wing imaginal disc, which revealed a unique phenomenon whereby cells at a distance from the injury upregulate caspase activity in a process called Necrosis-induced Apoptosis (NiA) that is vital for regeneration. This study further investigated this phenomenon, showing that NiA is predominantly associated with the highly regenerative pouch region of the disc, shaped by genetic factors present in the presumptive hinge. Furthermore, this study found that a proportion of NiA fail to undergo apoptosis, instead surviving effector caspase activation to persist within the tissue and stimulate reparative proliferation late in regeneration. This proliferation relies on the initiator caspase Dronc, and occurs independent of JNK, ROS or mitogens associated with the previously characterized Apoptosis-induced Proliferation (AiP) mechanism. These data reveal a new means by which non-apoptotic Dronc signaling promotes regenerative proliferation in response to necrotic damage. |
| Vicidomini, R., Choudhury, S. D., Han, T. H., Nguyen, T. H., Nguyen, P., Opazo, F., Serpe, M. (2024). Versatile nanobody-based approach to image, track and reconstitute functional Neurexin-1 in vivo. Nat Commun, 15(1):6068 PubMed ID: 39025931
Summary: Neurexins are key adhesion proteins that coordinate extracellular and intracellular synaptic components. Nonetheless, the low abundance of these multidomain proteins has complicated any localization and structure-function studies. This study combines an ALFA tag (AT)/nanobody (NbALFA) tool with classic genetics, cell biology and electrophysiology to examine the distribution and function of the Drosophila Nrx-1 in vivo. Full-length and ΔPDZ ALFA-tagged Nrx-1 variants were generated, and it was found that the PDZ binding motif is key to Nrx-1 surface expression. A PDZ binding motif provided in trans, via genetically encoded cytosolic NbALFA-PDZ chimera, fully restores the synaptic localization and function of Nrx(ΔPDZ-AT). Using cytosolic NbALFA-mScarlet intrabody, compartment-specific detection was achieved of endogenous Nrx-1, live Nrx-1 transport was tracked along the motor neuron axons, and Nrx-1 was demonstrated to co-migrate with Rab2-positive vesicles. These findings illustrate the versatility of the ALFA system and pave the way towards dissecting functional domains of complex proteins in vivo. | Schwartz, M., Petiot, N., Chaloyard, J., Senty-Segault, V., Lirussi, F., Senet, P., Nicolai, A., Heydel, J. M., Canon, F., Sonkaria, S., Khare, V., Didierjean, C., Neiers, F. (2024). Structural and Thermodynamic Insights into Dimerization Interfaces of Drosophila Glutathione Transferases. Biomolecules, 14(7) PubMed ID: 39062472
Summary: This study presents a comprehensive analysis of the dimerization interfaces of fly Glutathione S-Transferases (GSTs) through sequence alignment. GSTE1 is revealed to be a particularly intriguing target, providing valuable insights into the variations within Delta and Epsilon GST interfaces. The X-ray structure of GSTE1 was determined, unveiling remarkable thermal stability and a distinctive dimerization interface. Utilizing circular dichroism, the thermal stability of GSTE1 and other Drosophila GSTs with resolved X-ray structures was assessed. The subsequent examination of GST dimer stability correlated with the dimerization interface supported by findings from X-ray structural analysis and thermal stability measurements. A discussion extends to the broader context of GST dimer interfaces, offering a generalized perspective on their stability. This research enhances understanding of the structural and thermodynamic aspects of GST dimerization, contributing valuable insights to the field. |
| Ostale, C. M., Pulido, D., Vega-Cuesta, P., Lopez-Varea, A., de Celis, J. F. (2024). Developmental analysis of Spalt function in the Drosophila prothoracic gland. Development, 151(16) PubMed ID: 39087588
Summary: Spalt transcriptional regulators participate in a variety of cell fate specification processes during development, regulating transcription through interactions with DNA AT-rich regions. Spalt proteins also bind to heterochromatic regions, and some of their effects require interactions with the NuRD chromatin remodeling and deacetylase complex. Most of the biological roles of Spalt proteins have been characterized in diploid cells engaged in cell proliferation. This study addresses the function of Drosophila Spalt genes in the development of a larval tissue formed by polyploid cells, the prothoracic gland, the cells of which undergo several rounds of DNA replication without mitosis during larval development. Prothoracic glands depleted of Spalt expression display severe changes in the size of the nucleolus, the morphology of the nuclear envelope and the disposition of the chromatin within the nucleus, leading to a failure in the synthesis of ecdysone. It is proposed that loss of ecdysone production in the prothoracic gland of Spalt mutants is primarily caused by defects in nuclear pore complex function that occur as a consequence of faulty interactions between heterochromatic regions and the nuclear envelope. | Bellah, S. F., Yang, F., Xiong, F., Dou, Z., Yao, X., Liu, X. (2024). ZW10: an emerging orchestrator of organelle dynamics during the cell division cycle. J Mol Cell Biol, PubMed ID: 38830800
Summary: Zeste white 10 (ZW10) was first identified as a centromere/kinetochore protein encoded by the ZW10 gene in Drosophila. ZW10 guides the spindle assembly checkpoint signaling during mitotic chromosome segregation in metazoans. Recent studies have shown that ZW10 is also involved in membranous organelle interactions during interphase and plays a vital role in membrane transport between the endoplasmic reticulum and Golgi apparatus. Despite these findings, the precise molecular mechanisms by which ZW10 regulates interactions between membranous organelles in interphase and the assembly of membraneless organelle kinetochore in mitosis remain elusive. This study highlights how ZW10 forms context-dependent protein complexes during the cell cycle. These complexes are essential for mediating membrane trafficking in interphase and ensuring the accurate segregation of chromosomes in mitosis. |
Wednesday, June 11th - Adult Neural Structure, Development and Function |
| Chang, Y. C., Peng, Y. J., Lee, J. Y., Chag, K. T. (2024). Peripheral glia and neurons jointly regulate activity-induced synaptic remodeling at the Drosophila neuromuscular junction. bioRxiv, PubMed ID: 39005352
Summary: In the nervous system, reliable communication depends on the ability of neurons to adaptively remodel their synaptic structure and function in response to changes in neuronal activity. While neurons are the main drivers of synaptic plasticity, glial cells are increasingly recognized for their roles as active modulators. However, the underlying molecular mechanisms remain unclear. Using Drosophila neuromuscular junction as a model system for a tripartite synapse, this study showed that peripheral glial cells collaborate with neurons at the NMJ to regulate activity-induced synaptic remodeling, in part through a protein called shriveled (Shv). Shv is an activator of integrin signaling previously shown to be released by neurons during intense stimulation at the fly NMJ to regulate activity-induced synaptic remodeling. This study demonstrated that Shv is also present in peripheral glia, and glial Shv is both necessary and sufficient for synaptic remodeling. However, unlike neuronal Shv, glial Shv does not activate integrin signaling at the NMJ. Instead, it regulates synaptic plasticity in two ways: 1) maintaining the extracellular balance of neuronal Shv proteins to regulate integrin signaling, and 2) controlling ambient extracellular glutamate concentration to regulate postsynaptic glutamate receptor abundance. Loss of glial cells showed the same phenotype as loss of Shv in glia. Together, these results reveal that neurons and glial cells homeostatically regulate extracellular Shv protein levels to control activity-induced synaptic remodeling. Additionally, peripheral glia maintains postsynaptic glutamate receptor abundance and contribute to activity-induced synaptic remodeling by regulating ambient glutamate concentration at the fly NMJ. | Kaneko, T., Li, R., He, Q., Yang, L., Ye, B. (2024). Transsynaptic BMP Signaling Regulates Fine-Scale
Topography between Adjacent Sensory Neurons. eNeuro, 11(8) PubMed ID: 39137988
Summary: Sensory axons projecting to the central nervous system are organized into topographic maps that represent the locations of sensory stimuli. In some sensory systems, even adjacent sensory axons are arranged topographically, forming "fine-scale" topographic maps. Although several broad molecular gradients are known to instruct coarse topography, little is known about the molecular signaling that regulates fine-scale topography at the level of two adjacent axons. This study provides evidence that transsynaptic bone morphogenetic protein (BMP) signaling mediates local interneuronal communication to regulate fine-scale topography in the nociceptive system of Drosophila larvae. The topographic separation of the axon terminals of adjacent nociceptors requires their common postsynaptic target, the A08n neurons. This phenotype is recapitulated by knockdown of the BMP ligand, Decapentaplegic (Dpp), in these neurons. In addition, removing the Type 2 BMP receptors or their effector (Mad transcription factor) in single nociceptors impairs the fine-scale topography, suggesting the contribution of BMP signaling originated from A08n. This signaling is likely mediated by phospho-Mad in the presynaptic terminals of nociceptors to ensure local interneuronal communication. Finally, reducing Dpp levels in A08n reduces the nociceptor-A08n synaptic contacts. These data support that transsynaptic BMP signaling establishes the fine-scale topography by facilitating the formation of topographically correct synapses. Local BMP signaling for synapse formation may be a developmental strategy that independently regulates neighboring axon terminals for fine-scale topography. |
| Boerner, J., Robbins, K., Murphey, R. (2024). Laser Cell Ablation in Intact Drosophila Larvae Reveals Synaptic Competition. J Vis Exp, (209) PubMed ID: 39141541
Summary: The protocol describes single-neuron ablation with a 2-photon laser system in the central nervous system (CNS) of intact Drosophila melanogaster larvae. Using this non-invasive method, the developing nervous system can be manipulated in a cell-specific manner. Disrupting the development of individual neurons in a network can be used to study how the nervous system can compensate for the loss of synaptic input. Individual neurons were specifically ablated in the giant fiber system of Drosophila, with a focus on two neurons: the presynaptic giant fiber (GF) and the postsynaptic tergotrochanteral motor neuron (TTMn). The GF synapses with the ipsilateral TTMn, which is crucial to the escape response. Ablating one of the GFs in the 3(rd) instar brain, just after the GF starts axonal growth, permanently removes the cell during the development of the CNS. The remaining GF reacts to the absent neighbor and forms an ectopic synaptic terminal to the contralateral TTMn. This atypical, bilaterally symmetric terminal innervates both TTMns, as demonstrated by dye coupling, and drives both motor neurons, as demonstrated by electrophysiological assays. In summary, the ablation of a single interneuron demonstrates synaptic competition between a bilateral pair of neurons that can compensate for the loss of one neuron and restore normal responses to the escape circuit. | Welch, L. G., Muschalik, N., Munro, S. (2024). The FAM114A proteins are adaptors for the recycling of Golgi enzymes. J Cell Sci, 137(17) PubMed ID: 39129673
Summary: Golgi-resident enzymes remain in place while their substrates flow through from the endoplasmic reticulum to elsewhere in the cell. COPI-coated vesicles bud from the Golgi to recycle Golgi residents to earlier cisternae. Different enzymes are present in different parts of the stack, and one COPI adaptor protein, GOLPH3 (see Drosophila sauron), acts to recruit enzymes into vesicles in part of the stack. This study used proximity biotinylation to identify further components of intra-Golgi vesicles and found FAM114A2, a cytosolic protein. Affinity chromatography with FAM114A2, and its paralogue FAM114A1, showed that they bind to Golgi-resident membrane proteins, with membrane-proximal basic residues in the cytoplasmic tail being sufficient for the interaction. Deletion of both proteins from U2OS cells did not cause substantial defects in Golgi function. However, a Drosophila orthologue of these proteins (CG9590/FAM114A) is also localised to the Golgi and binds directly to COPI. Drosophila mutants lacking FAM114A have defects in glycosylation of glue proteins in the salivary gland. Thus, the FAM114A proteins bind Golgi enzymes and are candidate adaptors to contribute specificity to COPI vesicle recycling in the Golgi stack. |
| Xu, C., Li, Z., Lyu, C., Hu, Y., McLaughlin, C. N., Wong, K. K. L., Xie, Q., Luginbuhl, D. J., Li, H., Udeshi, N. D., Svinkina, T., Mani, D. R., Han, S., Li, T., Li, Y., Guajardo, R., Ting, A. Y., Carr, S. A., Li, J., Luo, L. (2024). Molecular and cellular mechanisms of teneurin signaling in synaptic partner matching. Cell, 187(18):5081-5101 PubMed ID: 38996528
Summary: In developing brains, axons exhibit remarkable precision in selecting synaptic partners among many non-partner cells. Evolutionarily conserved teneurins are transmembrane proteins that instruct synaptic partner matching. However, how intracellular signaling pathways execute teneurins' functions is unclear. HThis study used in situ proximity labeling to obtain the intracellular interactome of a teneurin (Ten-m) in the Drosophila brain. Genetic interaction studies using quantitative partner matching assays in both olfactory receptor neurons (ORNs) and projection neurons (PNs) reveal a common pathway: Ten-m binds to and negatively regulates a RhoGAP, thus activating the Rac1 small GTPases to promote synaptic partner matching. Developmental analyses with single-axon resolution identify the cellular mechanism of synaptic partner matching: Ten-m signaling promotes local F-actin levels and stabilizes ORN axon branches that contact partner PN dendrites. Combining spatial proteomics and high-resolution phenotypic analyses, this study advanced understanding of both cellular and molecular mechanisms of synaptic partner matching. | Mou, W., Cui, Y. (2024). Enhancing neuronal reticulophagy: a strategy for combating aging and APP toxicity. Autophagy, 20(12):2819-2820 PubMed ID: 38963012
Summary: Reticulophagy, which directs the endoplasmic reticulum (ER) to the phagophore for sequestration within an autophagosome and subsequent lysosomal degradation via specific receptors, is essential for ER quality control and is implicated in various diseases. This study utilizes Drosophila to establish an in vivo model for reticulophagy. Starvation-induced reticulophagy is detected across multiple tissues in Drosophila. Whole-body upregulation or downregulation of the expression of reticulophagy receptors, atl and Rtnl1, negatively affects fly health. Notably, moderate upregulation of reticulophagy in neuronal tissues by overexpressing these receptors reduces age-related degeneration. In a Drosophila Alzheimer model expressing human APP (amyloid beta precursor protein), reticulophagy is compromised. Correcting reticulophagy by enhancing atl and Rtnl1 expression in the neurons promotes APP degradation, significantly reducing neurodegenerative symptoms. However, overexpression of mutated atl and Rtnl1 , which disrupts the interaction of the corresponding proteins with Atg8, does not alleviate these symptoms, emphasizing the importance of receptor functionality. These findings support modulating reticulophagy as a therapeutic strategy for aging and neurodegenerative diseases associated with ER protein accumulation. |
Tuesday June 10th - Immune Response |
| Chasse, A. Y., Bandyadka, S., Wertheimer, M. C., Serizier, S. B., McCall, K. (2024). Professional phagocytes are recruited for the clearance of obsolete nonprofessional phagocytes in the Drosophila ovary. Frontiers in immunology 15:1389674 PubMed ID: 38994369
Summary: Cell death is an important process in the body, as it occurs throughout every tissue during development, disease, and tissue regeneration. Phagocytes are responsible for clearing away dying cells and are typically characterized as either professional or nonprofessional phagocytes. Professional phagocytes, such as macrophages, are found in nearly every part of the body while nonprofessional phagocytes, such as epithelial cells, are found in every tissue type. However, there are organs that are considered "immune-privileged" as they have little to no immune surveillance and rely on nonprofessional phagocytes to engulf dying cells. These organs are surrounded by barriers to protect the tissue from viruses, bacteria, and perhaps even immune cells. The Drosophila ovary is considered immune-privileged, however the presence of hemocytes, the macrophages of Drosophila, around the ovary suggests they may have a potential function. This study analyze hemocyte localization and potential functions in response to starvation-induced cell death in the ovary. Hemocytes were found to accumulate in the oviduct in the vicinity of mature eggs and follicle cell debris. Genetic ablation of hemocytes revealed that the presence of hemocytes affects oogenesis and that they phagocytose ovarian cell debris and in their absence fecundity decreases. Unpaired3, an IL-6 like cytokine, was found to be required for the recruitment of hemocytes to the oviduct to clear away obsolete follicle cells. These findings demonstrate a role for hemocytes in the ovary, providing a more thorough understanding of phagocyte communication and cell clearance in a previously thought immune-privileged organ. | Yao, X., He, Y., Zhu, C., Yang, S., Wu, J., Ma, F., Jin, P. (2024). miR-190 restores the innate immune homeostasis of Drosophila by directly inhibiting Tab2 in Imd pathway. Microbes and infection:105399 PubMed ID: 39084397
Summary: The Drosophila Imd pathways are well-known mechanisms involved in innate immunity responsible for Gram-negative (G-) bacterial infection. The intensity and durability of immunity need to be finely regulated to keep sufficient immune activation meanwhile avoid excessive immune response. This study firstly demonstrated that miR-190 can downregulate the expression levels of antimicrobial peptides (AMPs) in the Imd immune pathway after Escherichia coli infection using the miR-190 overexpression flies and the miR-190KO/+ flies. Secondly, miR-190 overexpression significantly reduces while miR-190 KO increases Drosophila survival rates upon lethal Enterobacter cloacae infection. Thirdly, this study further demonstrated that miR-190 negatively regulates innate immune responses by directly targeting both RA/RB and RC isoforms of Tab2. In addition, the dynamic expression pattern of AMPs (Dpt, AttA, CecA1), miR-190 and Tab2 in the wild-type flies reveals that miR-190 play an important role in Drosophila immune homeostasis restoration at the late stage of E. coli infection. Collectively, this study reveals that miR-190 can downregulate the expression of AMPs by targeting Tab2 and promote immune homeostasis restoration in Drosophila Imd pathway. This study provides new insights into the regulatory mechanism of animal innate immune homeostasis. |
| Mallick, S., Kenney, E., Eleftherianos, I. (2024). The Activin Branch Ligand Daw Regulates the Drosophila melanogaster Immune Response and Lipid Metabolism against the Heterorhabditis bacteriophora Serine Carboxypeptidase. Int J Mol Sci, 25(14) PubMed ID: 39063211
Summary: Despite impressive advances in the broad field of innate immunity, understanding of the molecules and signaling pathways that control the host immune response to nematode infection remains incomplete. Recent work has shown that Transforming Growth Factor-β (TGF-β) signaling in the fruit fly Drosophila melanogaster is activated by nematode infection and certain TGF-β superfamily members regulate the D. melanogaster anti-nematode immune response. This study investigated the effect of an entomopathogenic nematode infection factor on host TGF-β pathway regulation and immune function. Heterorhabditis bacteriophora serine carboxypeptidase activates the Activin branch in D. melanogaster adults and the immune deficiency pathway in Activin-deficient flies. The carboxypeptidase affects hemocyte numbers and survival in flies deficient for Activin signaling, and causes increased intestinal steatosis in Activin-deficient flies. Thus, insights into the D. melanogaster signaling pathways and metabolic processes interacting with H. bacteriophora pathogenicity factors will be applicable to entomopathogenic nematode infection of important agricultural insect pests and vectors of disease. | Wang, X., Wei, D., Pan, Y., Liu, J., Xiao, X., Xia, Q., Wang, F. (2024). A cryptic homotypic interaction motif of insect STING is required for its antiviral signaling. Dev Comp Immunol, 159:105224 PubMed ID: 38969190
Summary: Stimulator of interferon genes (STING) mediates innate immune response upon binding to cyclic GMP-AMP (cGAMP). It recruits tank-binding kinase 1 (TBK1) and transcription factor interferon regulatory factor 3 (IRF3) through its C-terminal tail and facilitates TBK1-dependent phosphorylation of IRF3 via forming STING polymers in mammalian cells. However, the mechanism behind STING-mediated activation of NF-kappaB transcription factor, Relish, in insect cells is unknown. This study revealed that insect STING formed oligomers and the cryptic RIP homotypic interaction motif (cRHIM) was required for its oligomerization and its anti-viral functions. Cells expressing cRHIM-deficient mutants exhibited lower levels of anti-viral molecules, higher viral load after viral infection and weak activation of Relish. Moreover, under cGAMP stimulation, insect STING interacted with IMD, and deletion of the cRHIM motif on either protein prevented this interaction. Finally, this study demonstrated that cGAMP enhanced the amyloid-like property of insect STING aggregates by ThT staining. In summary, this research showed that insect STING employed a homotypic motif to form intermolecular interactions that are essential for its antiviral signaling. |
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