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PLoS Pathogens Jun 2024Invertebrates lack the immune machinery underlying vertebrate-like acquired immunity. However, in many insects past infection by the same pathogen can 'prime' the immune...
Invertebrates lack the immune machinery underlying vertebrate-like acquired immunity. However, in many insects past infection by the same pathogen can 'prime' the immune response, resulting in improved survival upon reinfection. Here, we investigated the mechanistic basis and epidemiological consequences of innate immune priming in the fruit fly Drosophila melanogaster when infected with the gram-negative bacterial pathogen Providencia rettgeri. We find that priming in response to P. rettgeri infection is a long-lasting and sexually dimorphic response. We further explore the epidemiological consequences of immune priming and find it has the potential to curtail pathogen transmission by reducing pathogen shedding and spread. The enhanced survival of individuals previously exposed to a non-lethal bacterial inoculum coincided with a transient decrease in bacterial loads, and we provide strong evidence that the effect of priming requires the IMD-responsive antimicrobial-peptide Diptericin-B in the fat body. Further, we show that while Diptericin B is the main effector of bacterial clearance, it is not sufficient for immune priming, which requires regulation of IMD by peptidoglycan recognition proteins. This work underscores the plasticity and complexity of invertebrate responses to infection, providing novel experimental evidence for the effects of innate immune priming on population-level epidemiological outcomes.
Topics: Animals; Immunity, Innate; Drosophila melanogaster; Providencia; Drosophila Proteins; Female; Male; Enterobacteriaceae Infections; Antimicrobial Peptides
PubMed: 38857285
DOI: 10.1371/journal.ppat.1012308 -
ArXiv May 2024Morphogenesis is the process whereby the body of an organism develops its target shape. The morphogen BMP is known to play a conserved role across bilaterian organisms...
Morphogenesis is the process whereby the body of an organism develops its target shape. The morphogen BMP is known to play a conserved role across bilaterian organisms in determining the dorsoventral (DV) axis. Yet, how BMP governs the spatio-temporal dynamics of cytoskeletal proteins driving morphogenetic flow remains an open question. Here, we use machine learning to mine a morphodynamic atlas of Drosophila development, and construct a mathematical model capable of predicting the coupled dynamics of myosin, E-cadherin, and morphogenetic flow. Mutant analysis shows that BMP sets the initial condition of this dynamical system according to the following signaling cascade: BMP establishes DV pair-rule-gene patterns that set-up an E-cadherin gradient which in turn creates a myosin gradient in the opposite direction through mechanochemical feedbacks. Using neural tube organoids, we argue that BMP, and the signaling cascade it triggers, prime the conserved dynamics of neuroectoderm morphogenesis from fly to humans.
PubMed: 38855544
DOI: No ID Found -
Genome Biology and Evolution Jun 2024Ovaries play key roles in fitness and evolution: they are essential female reproductive structures that develop and house the eggs in sexually reproducing animals. In...
Ovaries play key roles in fitness and evolution: they are essential female reproductive structures that develop and house the eggs in sexually reproducing animals. In Drosophila, the mature ovary contains multiple tubular egg-producing structures known as ovarioles. Ovarioles arise from somatic cellular structures in the larval ovary called terminal filaments, formed by terminal filament cells and subsequently enclosed by sheath cells. As in many other insects, ovariole number per female varies extensively in Drosophila. At present however, there is a striking gap of information on genetic mechanisms and evolutionary forces that shape the well-documented rapid interspecies divergence of ovariole numbers. To address this gap, here we studied genes associated with D. melanogaster ovariole number or functions based on recent experimental and transcriptional datasets from larval ovaries, including terminal filaments and sheath cells, and assessed their rates and patterns of molecular evolution in five closely related species of the melanogaster subgroup that exhibit species-specific differences in ovariole numbers. From comprehensive analyses of protein sequence evolution (dN/dS), branch-site positive selection, expression specificity (tau) and phylogenetic regressions (PGLS), we report evidence of 42 genes that showed signs of playing roles in the genetic basis of interspecies evolutionary change of Drosophila ovariole number. These included the signalling genes upd2 and Ilp5 and extracellular matrix genes vkg and Col4a1, whose dN/dS predicted ovariole numbers among species. Together, we propose a model whereby a set of ovariole-involved gene proteins have an enhanced evolvability, including adaptive evolution, facilitating rapid shifts in ovariole number among Drosophila species.
PubMed: 38848313
DOI: 10.1093/gbe/evae118 -
ELife Jun 2024The atypical cadherins Fat and Dachsous (Ds) signal through the Hippo pathway to regulate growth of numerous organs, including the wing. Here, we find that Ds-Fat...
The atypical cadherins Fat and Dachsous (Ds) signal through the Hippo pathway to regulate growth of numerous organs, including the wing. Here, we find that Ds-Fat signaling tunes a unique feature of cell proliferation found to control the rate of wing growth during the third instar larval phase. The duration of the cell cycle increases in direct proportion to the size of the wing, leading to linear-like growth during the third instar. Ds-Fat signaling enhances the rate at which the cell cycle lengthens with wing size, thus diminishing the rate of wing growth. We show that this results in a complex but stereotyped relative scaling of wing growth with body growth in . Finally, we examine the dynamics of Fat and Ds protein distribution in the wing, observing graded distributions that change during growth. However, the significance of these dynamics is unclear since perturbations in expression have negligible impact on wing growth.
Topics: Animals; Wings, Animal; Drosophila Proteins; Cell Cycle; Signal Transduction; Drosophila melanogaster; Cadherins; Larva; Cell Proliferation; Cell Adhesion Molecules
PubMed: 38842917
DOI: 10.7554/eLife.91572 -
Biology Open Jun 2024Bazooka/Par-3 (Baz) is an evolutionarily conserved scaffold protein that functions as a master regulator for the establishment and maintenance of cell polarity in many...
Bazooka/Par-3 (Baz) is an evolutionarily conserved scaffold protein that functions as a master regulator for the establishment and maintenance of cell polarity in many different cell types. In the vast majority of published research papers Baz has been reported to localize at the cell cortex and at intercellular junctions. However, there have also been several reports showing localization and function of Baz at additional subcellular sites, in particular the nuclear envelope and the neuromuscular junction. In this study we have re-assessed the localization of Baz to these subcellular sites in a systematic manner. We used antibodies raised in different host animals against different epitopes of Baz for confocal imaging of Drosophila tissues. We tested the specificity of these antisera by mosaic analysis with null mutant baz alleles and tissue-specific RNAi against baz. In addition, we used a GFP-tagged gene trap line for Baz and a bacterial artificial chromosome (BAC) expressing GFP-tagged Baz under control of its endogenous promoter in a baz mutant background to compare the subcellular localization of the GFP-Baz fusion proteins to the staining with anti-Baz antisera. Together, these experiments did not provide evidence for specific localization of Baz to the nucleus or the neuromuscular junction.
Topics: Animals; Cell Nucleus; Drosophila Proteins; Neuromuscular Junction; Protein Transport; Drosophila melanogaster
PubMed: 38841912
DOI: 10.1242/bio.060544 -
Nature Jun 2024Histone acetylation regulates gene expression, cell function and cell fate. Here we study the pattern of histone acetylation in the epithelial tissue of the Drosophila...
Histone acetylation regulates gene expression, cell function and cell fate. Here we study the pattern of histone acetylation in the epithelial tissue of the Drosophila wing disc. H3K18ac, H4K8ac and total lysine acetylation are increased in the outer rim of the disc. This acetylation pattern is controlled by nuclear position, whereby nuclei continuously move from apical to basal locations within the epithelium and exhibit high levels of H3K18ac when they are in proximity to the tissue surface. These surface nuclei have increased levels of acetyl-CoA synthase, which generates the acetyl-CoA for histone acetylation. The carbon source for histone acetylation in the rim is fatty acid β-oxidation, which is also increased in the rim. Inhibition of fatty acid β-oxidation causes H3K18ac levels to decrease in the genomic proximity of genes involved in disc development. In summary, there is a physical mark of the outer rim of the wing and other imaginal epithelia in Drosophila that affects gene expression.
Topics: Animals; Acetate-CoA Ligase; Acetyl Coenzyme A; Acetylation; Biological Transport; Cell Nucleus; Chromatin; Drosophila melanogaster; Drosophila Proteins; Fatty Acids; Gene Expression Regulation; Histones; Imaginal Discs; Lysine; Oxidation-Reduction; Wings, Animal
PubMed: 38839952
DOI: 10.1038/s41586-024-07471-4 -
Development (Cambridge, England) Jun 2024Germline maintenance relies on adult stem cells to continually replenish lost gametes over a lifetime and respond to external cues altering the demands on the tissue....
Germline maintenance relies on adult stem cells to continually replenish lost gametes over a lifetime and respond to external cues altering the demands on the tissue. Mating worsens germline homeostasis over time, yet a negative impact on stem cell behavior has not been explored. Using extended live imaging of the Drosophila testis stem cell niche, we find that short periods of mating in young males disrupts cytokinesis in germline stem cells (GSCs). This defect leads to failure of abscission, preventing release of differentiating cells from the niche. We find that GSC abscission failure is caused by increased Ecdysone hormone signaling induced upon mating, which leads to disrupted somatic encystment of the germline. Abscission failure is rescued by isolating males from females, but recurs with resumption of mating. Importantly, reiterative mating also leads to increased GSC loss, requiring increased restoration of stem cells via symmetric renewal and de-differentiation. Together, these results suggest a model whereby acute mating results in hormonal changes that negatively impact GSC cytokinesis but preserves the stem cell population.
Topics: Animals; Cytokinesis; Male; Ecdysone; Testis; Female; Drosophila melanogaster; Germ Cells; Stem Cell Niche; Stem Cells; Cell Differentiation; Signal Transduction; Drosophila Proteins
PubMed: 38832826
DOI: 10.1242/dev.202542 -
Biochemistry. Biokhimiia Apr 2024Dosage compensation complex (DCC), which consists of five proteins and two non-coding RNAs roX, specifically binds to the X chromosome in males, providing a higher level...
Dosage compensation complex (DCC), which consists of five proteins and two non-coding RNAs roX, specifically binds to the X chromosome in males, providing a higher level of gene expression necessary to compensate for the monosomy of the sex chromosome in male Drosophila compared to the two X chromosomes in females. The MSL2 protein contains the N-terminal RING domain, which acts as an E3 ligase in ubiquitination of proteins and is the only subunit of the complex expressed only in males. Functional role of the two C-terminal domains of the MSL2 protein, enriched with proline (P-domain) and basic amino acids (B-domain), was investigated. As a result, it was shown that the B-domain destabilizes the MSL2 protein, which is associated with the presence of two lysines ubiquitination of which is under control of the RING domain of MSL2. The unstructured proline-rich domain stimulates transcription of the roX2 gene, which is necessary for effective formation of the dosage compensation complex.
Topics: Animals; Drosophila Proteins; Drosophila melanogaster; Protein Domains; Male; Female; Transcription Factors; Ubiquitination; DNA-Binding Proteins
PubMed: 38831503
DOI: 10.1134/S0006297924040060 -
Biochemistry. Biokhimiia Apr 2024Su(Hw) belongs to the class of proteins that organize chromosome architecture, determine promoter activity, and participate in formation of the boundaries/insulators...
Su(Hw) belongs to the class of proteins that organize chromosome architecture, determine promoter activity, and participate in formation of the boundaries/insulators between the regulatory domains. This protein contains a cluster of 12 zinc fingers of the C2H2 type, some of which are responsible for binding to the consensus site. The Su(Hw) protein forms complex with the Mod(mdg4)-67.2 and the CP190 proteins, where the last one binds to all known Drosophila insulators. To further study functioning of the Su(Hw)-dependent complexes, we used the previously described su(Hw) mutation with inactive seventh zinc finger, which produces mutant protein that cannot bind to the consensus site. The present work shows that the Su(Hw) protein continues to directly interact with the CP190 and Mod(mdg4)-67.2 proteins. Through interaction with Mod(mdg4)-67.2, the Su(Hw) protein can be recruited into the Su(Hw)-dependent complexes formed on chromatin and enhance their insulator activity. Our results demonstrate that the Su(Hw) dependent complexes without bound DNA can be recruited to the Su(Hw) binding sites through the specific protein-protein interactions that are stabilized by Mod(mdg4)-67.2.
Topics: Drosophila Proteins; Animals; Chromatin; Transcription Factors; Drosophila melanogaster; Repressor Proteins; Protein Binding; Nuclear Proteins; DNA-Binding Proteins; Zinc Fingers; Microtubule-Associated Proteins
PubMed: 38831500
DOI: 10.1134/S0006297924040035 -
Cell Death & Disease Jun 2024Vitamin B6 is a water-soluble vitamin which possesses antioxidant properties. Its catalytically active form, pyridoxal 5'-phosphate (PLP), is a crucial cofactor for DNA...
Vitamin B6 is a water-soluble vitamin which possesses antioxidant properties. Its catalytically active form, pyridoxal 5'-phosphate (PLP), is a crucial cofactor for DNA and amino acid metabolism. The inverse correlation between vitamin B6 and cancer risk has been observed in several studies, although dietary vitamin B6 intake sometimes failed to confirm this association. However, the molecular link between vitamin B6 and cancer remains elusive. Previous work has shown that vitamin B6 deficiency causes chromosome aberrations (CABs) in Drosophila and human cells, suggesting that genome instability may correlate the lack of this vitamin to cancer. Here we provide evidence in support of this hypothesis. Firstly, we show that PLP deficiency, induced by the PLP antagonists 4-deoxypyridoxine (4DP) or ginkgotoxin (GT), promoted tumorigenesis in eye larval discs transforming benign Ras tumors into aggressive forms. In contrast, PLP supplementation reduced the development of tumors. We also show that low PLP levels, induced by 4DP or by silencing the sgll gene involved in PLP biosynthesis, worsened the tumor phenotype in another Drosophila cancer model generated by concomitantly activating Ras and downregulating Discs-large (Dlg) gene. Moreover, we found that Ras eye discs from larvae reared on 4DP displayed CABs, reactive oxygen species (ROS) and low catalytic activity of serine hydroxymethyltransferase (SHMT), a PLP-dependent enzyme involved in thymidylate (dTMP) biosynthesis, in turn required for DNA replication and repair. Feeding Ras 4DP-fed larvae with PLP or ascorbic acid (AA) plus dTMP, rescued both CABs and tumors. The same effect was produced by overexpressing catalase in Ras Dlg 4DP-fed larvae, thus allowing to establish a relationship between PLP deficiency, CABs, and cancer. Overall, our data provide the first in vivo demonstration that PLP deficiency can impact on cancer by increasing genome instability, which is in turn mediated by ROS and reduced dTMP levels.
Topics: Animals; Vitamin B 6 Deficiency; Drosophila Proteins; Vitamin B 6; Drosophila melanogaster; Drosophila; Pyridoxal Phosphate; Reactive Oxygen Species; Carcinogenesis; ras Proteins; Neoplasms; Larva; Humans
PubMed: 38830901
DOI: 10.1038/s41419-024-06787-3