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Bioinformatic and functional analyses of muscle cell diversification in Drosophila melanogaster

Abstract : The voluntary skeletal muscles in vertebrates are the main effectors of locomotion. Processes and genes implicated in human myogenesis are of immense interest to better understand the deregulations caused in muscular and neuromuscular disorders and to find therapeutic targets. The body wall or somatic muscles of the fruit fly, Drosophila melanogaster, are similar to vertebrate skeletal muscles. As is the case for vertebrate skeletal muscles, each Drosophila embryonic somatic muscle possesses its specific identity that clearly distinguishes from its immediate neighbors. In Drosophila, some muscle identity transcription factors (iTFs) have been identified, but others remain elusive. In order to dissect mechanisms regulating the diversification of committed muscle cells to attain their final identity, the team had previously generated transcriptomics data for mRNA under translation in the Lms+ lateral transverse (LT) and Slou+ muscle subsets as well as the Duf+ global muscle set over three time windows of development. My analyses of this data helped identify the evolutionarily conserved gene that is part of the conserved Wnt enhanceosome, Sequence-specific single-stranded DNA-binding protein (Ssdp) as a determinant of final muscle identity. Its vertebrate homologue Single stranded DNA binding protein 3 (SSBP3) is downregulated and mis-spliced in human myotonic dystrophies, but its role in myogenesis has not been studied. My study reveals a role for Ssdp in embryonic myogenesis for the first time. A temporally regulated, isoform-specific expression of Ssdp was identified. Further analyses showed that the initial muscle identity program proceeds normally for the most part in the absence of zygotic Ssdp, but muscles fail to establish their final identity due to the deregulation of iTFs and identity processes that establish muscle morphology, innervation and attachment. Comparative analyses revealed that specific Ssdp mutant phenotypes overlap subsets of phenotypes observed in the context of loss of function of a Drosophila Wnt, Wg and dTCF, an effector of the canonical Wnt pathway, suggesting specific interactions between these factors. Potential genetic interactions between the LT iTF, Ap (a Lhx2 orthologue) with Mid and the Ssdp partner, Chi (a LDB1 orthologue, also part of the Wnt enhanceosome) were unveiled. In addition, my in silico analysis identified other potential candidates implicated in muscle identity such as the TFs D, Sox14 and Sox21b for LT muscles and Stat92E for Slou+ muscles, with Nf-YB acting as a potential upstream regulator. Muscle subset specific enrichments of CT-rich motifs in the LT subset and GATA motifs in the Slou subset were also identified.
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https://tel.archives-ouvertes.fr/tel-03279910
Contributor : Preethi Poovathumkadavil <>
Submitted on : Tuesday, July 6, 2021 - 6:18:38 PM
Last modification on : Thursday, July 8, 2021 - 3:57:21 PM

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Preethi Poovathumkadavil. Bioinformatic and functional analyses of muscle cell diversification in Drosophila melanogaster. Quantitative Methods [q-bio.QM]. Université Clermont Auvergne, 2021. English. ⟨tel-03279910⟩

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