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Current Opinion in Genetics &... Feb 2024Specifically timed pulses of the moulting hormone ecdysone are necessary for developmental progression in insects, guiding development through important milestones such... (Review)
Review
Specifically timed pulses of the moulting hormone ecdysone are necessary for developmental progression in insects, guiding development through important milestones such as larval moults, pupation and metamorphosis. It also coordinates the acquisition of cell identities, known as cell patterning, and growth in a tissue-specific manner. In the absence of ecdysone, the ecdysone receptor heterodimer Ecdysone Receptor and Ultraspiracle represses expression of target primary response genes, which become de-repressed as the ecdysone titre rises. However, ecdysone signalling elicits both repressive and activating responses in a temporal and tissue-specific manner. To understand how ecdysone achieves such specificity, this review explores the layers of gene regulation involved in stage-appropriate ecdysone responses in Drosophila fruit flies.
Topics: Animals; Drosophila; Ecdysone; Drosophila Proteins; Steroids; Gene Expression Regulation; Larva; Gene Expression Regulation, Developmental; Drosophila melanogaster
PubMed: 38271845
DOI: 10.1016/j.gde.2023.102148 -
The EMBO Journal Aug 2023Cilia are cellular projections that perform sensory and motile functions in eukaryotic cells. A defining feature of cilia is that they are evolutionarily ancient, yet...
Cilia are cellular projections that perform sensory and motile functions in eukaryotic cells. A defining feature of cilia is that they are evolutionarily ancient, yet not universally conserved. In this study, we have used the resulting presence and absence pattern in the genomes of diverse eukaryotes to identify a set of 386 human genes associated with cilium assembly or motility. Comprehensive tissue-specific RNAi in Drosophila and mutant analysis in C. elegans revealed signature ciliary defects for 70-80% of novel genes, a percentage similar to that for known genes within the cluster. Further characterization identified different phenotypic classes, including a set of genes related to the cartwheel component Bld10/CEP135 and two highly conserved regulators of cilium biogenesis. We propose this dataset defines the core set of genes required for cilium assembly and motility across eukaryotes and presents a valuable resource for future studies of cilium biology and associated disorders.
Topics: Animals; Humans; Drosophila; Caenorhabditis elegans; Phylogeny; Cilia; Drosophila Proteins
PubMed: 37317646
DOI: 10.15252/embj.2023113616 -
Autophagy Jul 2023Macroautophagy/autophagy is involved in many aspects of human development including the formation of neuronal circuits. A recent study from Dutta et al. found that the...
Macroautophagy/autophagy is involved in many aspects of human development including the formation of neuronal circuits. A recent study from Dutta et al. found that the recruitment of Egfr (Epidermal growth factor receptor) to synapses suppresses autophagic degradation of presynaptic proteins, a requirement for proper neuronal circuit development. The findings suggest that Egfr inactivation during a distinct critical interval in late development results in increased levels of autophagy in the brain and decreased neuronal circuit development. Furthermore, the presence of brp (bruchpilot) in the synapse is critical for proper neuronal functioning over this same period. Dutta and colleagues found that increased autophagy due to Egfr inactivation results in decreased brp levels and, therefore, reduced neuronal connectivity. Through live cell imaging, it was determined that only the synaptic branches that accumulate both Egfr and brp are stabilized, allowing for the persistence of active zones, further supporting the importance of both Egfr and brp in the brain. While Dutta and colleagues collected these data based on studies conducted on Drosophila brains, the findings provide great insight as to how these different proteins may be implicated in human neurology.
Topics: Animals; Humans; Autophagy; Synapses; Drosophila; Drosophila Proteins; ErbB Receptors
PubMed: 37243688
DOI: 10.1080/15548627.2023.2217015 -
Genetics Aug 2023Gamete formation is essential for sexual reproduction in metazoans. Meiosis in males gives rise to spermatids that must differentiate and individualize into mature...
Gamete formation is essential for sexual reproduction in metazoans. Meiosis in males gives rise to spermatids that must differentiate and individualize into mature sperm. In Drosophila melanogaster, individualization of interconnected spermatids requires the formation of individualization complexes that synchronously move along the sperm bundles. Here, we show that Mob4, a member of the Mps-one binder family, is essential for male fertility but has no detectable role in female fertility. We show that Mob4 is required for proper axonemal structure and its loss leads to male sterility associated with defective spermatid individualization and absence of mature sperm in the seminal vesicles. Transmission electron micrographs of developing spermatids following mob4RNAi revealed expansion of the outer axonemal microtubules such that the 9 doublets no longer remained linked to each other and defective mitochondrial organization. Mob4 is a STRIPAK component, and male fertility is similarly impaired upon depletion of the STRIPAK components, Strip and Cka. Expression of the human Mob4 gene rescues all phenotypes of Drosophila mob4 downregulation, indicating that the gene is evolutionarily and functionally conserved. Together, this suggests that Mob4 contributes to the regulation of the microtubule- and actin-cytoskeleton during spermatogenesis through the conserved STRIPAK complex. Our study advances the understanding of male infertility by uncovering the requirement for Mob4 in sperm individualization.
Topics: Animals; Female; Humans; Male; Adaptor Proteins, Signal Transducing; Drosophila; Drosophila melanogaster; Drosophila Proteins; Infertility, Male; Nerve Tissue Proteins; Semen; Spermatids; Spermatogenesis; Testis
PubMed: 37259670
DOI: 10.1093/genetics/iyad104 -
Proceedings of the National Academy of... Jul 2023Maturation from early to late endosomes depends on the exchange of their marker proteins Rab5 to Rab7. This requires Rab7 activation by its specific guanine nucleotide...
Maturation from early to late endosomes depends on the exchange of their marker proteins Rab5 to Rab7. This requires Rab7 activation by its specific guanine nucleotide exchange factor (GEF) Mon1-Ccz1. Efficient GEF activity of this complex on membranes depends on Rab5, thus driving Rab-GTPase exchange on endosomes. However, molecular details on the role of Rab5 in Mon1-Ccz1 activation are unclear. Here, we identify key features in Mon1 involved in GEF regulation. We show that the intrinsically disordered N-terminal domain of Mon1 autoinhibits Rab5-dependent GEF activity on membranes. Consequently, Mon1 truncations result in higher GEF activity in vitro and alterations in early endosomal structures in nephrocytes. A shift from Rab5 to more Rab7-positive structures in yeast suggests faster endosomal maturation. Using modeling, we further identify a conserved Rab5-binding site in Mon1. Mutations impairing Rab5 interaction result in poor GEF activity on membranes and growth defects in vivo. Our analysis provides a framework to understand the mechanism of Ras-related in brain (Rab) conversion and organelle maturation along the endomembrane system.
Topics: Animals; Vesicular Transport Proteins; rab GTP-Binding Proteins; Protein Transport; Saccharomyces cerevisiae Proteins; Endosomes; Saccharomyces cerevisiae; Drosophila; rab5 GTP-Binding Proteins; Drosophila Proteins; Guanine Nucleotide Exchange Factors
PubMed: 37463208
DOI: 10.1073/pnas.2303750120 -
Life Science Alliance Sep 2023The NSL complex is a transcriptional activator. Germline-specific knockdown of NSL complex subunits NSL1, NSL2, and NSL3 results in reduced piRNA production from a...
The NSL complex is a transcriptional activator. Germline-specific knockdown of NSL complex subunits NSL1, NSL2, and NSL3 results in reduced piRNA production from a subset of bidirectional piRNA clusters, accompanied by widespread transposon derepression. The piRNAs most transcriptionally affected by NSL2 and NSL1 RNAi map to telomeric piRNA clusters. At the chromatin level, these piRNA clusters also show decreased levels of H3K9me3, HP1a, and Rhino after NSL2 depletion. Using NSL2 ChIP-seq in ovaries, we found that this protein specifically binds promoters of telomeric transposons , , and Germline-specific depletion of NSL2 also led to a reduction in nuclear Piwi in nurse cells. Our findings thereby support a role for the NSL complex in promoting the transcription of piRNA precursors from telomeric piRNA clusters and in regulating Piwi levels in the Drosophila female germline.
Topics: Animals; Piwi-Interacting RNA; Drosophila melanogaster; Drosophila Proteins; RNA, Small Interfering; Drosophila; Telomere
PubMed: 37399316
DOI: 10.26508/lsa.202302194 -
Nature Communications Aug 2023Small interference RNAs are the key components of RNA interference, a conserved RNA silencing or viral defense mechanism in many eukaryotes. In Drosophila melanogaster,...
Small interference RNAs are the key components of RNA interference, a conserved RNA silencing or viral defense mechanism in many eukaryotes. In Drosophila melanogaster, Dicer-2 (DmDcr-2)-mediated RNAi pathway plays important roles in defending against viral infections and protecting genome integrity. During the maturation of siRNAs, two cofactors can regulate DmDcr-2's functions: Loqs-PD that is required for dsRNA processing, and R2D2 that is essential for the subsequent loading of siRNAs into effector Ago2 to form RISC complexes. However, due to the lack of structural information, it is still unclear whether R2D2 and Loqs-PD affect the functions of DmDcr-2 simultaneously. Here we present several cryo-EM structures of DmDcr-2/R2D2/Loqs-PD complex bound to dsRNAs with various lengths by the Helicase domain. These structures revealed that R2D2 and Loqs-PD can bind to different regions of DmDcr-2 without interfering with each other. Furthermore, the cryo-EM results demonstrate that these complexes can form large oligomers and assemble into fibers. The formation and depolymerization of these oligomers are associated with ATP hydrolysis. These findings provide insights into the structural mechanism of DmDcr-2 and its cofactors during siRNA processing.
Topics: Animals; DNA Helicases; Drosophila melanogaster; Drosophila Proteins; RNA Interference; RNA, Double-Stranded; RNA, Small Interfering; RNA-Binding Proteins
PubMed: 37633971
DOI: 10.1038/s41467-023-40919-1 -
Cold Spring Harbor Perspectives in... Jan 2024Glia play a crucial role in providing metabolic support to neurons across different species. To do so, glial cells isolate distinct neuronal compartments from systemic... (Review)
Review
Glia play a crucial role in providing metabolic support to neurons across different species. To do so, glial cells isolate distinct neuronal compartments from systemic signals and selectively transport specific metabolites and ions to support neuronal development and facilitate neuronal function. Because of their function as barriers, glial cells occupy privileged positions within the nervous system and have also evolved to serve as signaling intermediaries in various contexts. The fruit fly, , has significantly contributed to our understanding of glial barrier development and function. In this review, we will explore the formation of the glial sheath, blood-brain barrier, and nerve barrier, as well as the significance of glia-extracellular matrix interactions in barrier formation. Additionally, we will delve into the role of glia as signaling intermediaries in regulating nervous system development, function, and response to injury.
Topics: Animals; Drosophila melanogaster; Neuroglia; Neurons; Drosophila; Drosophila Proteins
PubMed: 38167424
DOI: 10.1101/cshperspect.a041423 -
Developmental Cell Oct 2023The Hippo pathway is an evolutionarily conserved regulator of tissue growth that integrates inputs from both polarity and actomyosin networks. An upstream activator of...
The Hippo pathway is an evolutionarily conserved regulator of tissue growth that integrates inputs from both polarity and actomyosin networks. An upstream activator of the Hippo pathway, Kibra, localizes at the junctional and medial regions of the apical cortex in epithelial cells, and medial accumulation promotes Kibra activity. Here, we demonstrate that cortical Kibra distribution is controlled by a tug-of-war between apical polarity and actomyosin dynamics. We show that while the apical polarity network, in part via atypical protein kinase C (aPKC), tethers Kibra at the junctional cortex to silence its activity, medial actomyosin flows promote Kibra-mediated Hippo complex formation at the medial cortex, thereby activating the Hippo pathway. This study provides a mechanistic understanding of the relationship between the Hippo pathway, polarity, and actomyosin cytoskeleton, and it offers novel insights into how fundamental features of epithelial tissue architecture can serve as inputs into signaling cascades that control tissue growth, patterning, and morphogenesis.
Topics: Animals; Actomyosin; Cell Polarity; Drosophila; Drosophila Proteins; Hippo Signaling Pathway; Protein Serine-Threonine Kinases; Signal Transduction
PubMed: 37729921
DOI: 10.1016/j.devcel.2023.08.029 -
Science (New York, N.Y.) Jul 2023Gene expression is controlled by the precise activation and repression of transcription. Repression is mediated by specialized transcription factors (TFs) that recruit...
Gene expression is controlled by the precise activation and repression of transcription. Repression is mediated by specialized transcription factors (TFs) that recruit co-repressors (CoRs) to silence transcription, even in the presence of activating cues. However, whether CoRs can dominantly silence all enhancers or display distinct specificities is unclear. In this work, we report that most enhancers in can be repressed by only a subset of CoRs, and enhancers classified by CoR sensitivity show distinct chromatin features, function, TF motifs, and binding. Distinct TF motifs render enhancers more resistant or sensitive to specific CoRs, as we demonstrate by motif mutagenesis and addition. These CoR-enhancer compatibilities constitute an additional layer of regulatory specificity that allows differential regulation at close genomic distances and is indicative of distinct mechanisms of transcriptional repression.
Topics: Animals; Chromatin; Drosophila melanogaster; Drosophila Proteins; Enhancer Elements, Genetic; Gene Expression Regulation, Developmental; Repressor Proteins; Amino Acid Motifs
PubMed: 37440660
DOI: 10.1126/science.adf6149