Defects in protein O‐mannosylation result in abnormal muscle contractions and aberrant neural sensory feedback in Drosophila

Abstract

Protein O‐mannosylation pathway is evolutionarily conserved in metazoan organisms. In a wide range of species, from Drosophila to humans, defects in protein O‐mannosylation was found to be associated with abnormal muscle and neural development, as well as postdevelopmental pathologies, including muscle degeneration. In humans, mutations in genes involved in the biosynthesis of O‐mannosyl glycans result in severe muscular dystrophies that are called dystroglycanopathies because of prominent defects in glycosylation and function of Dystroglycan, a cell membrane protein mediating interactions of cells with the extracellular matrix. While recent studies shed more light on important structural features of O‐mannosyl glycans and revealed numerous new targets of O‐mannosylation in mammals, the mechanisms that underlie functions of O‐mannosyl glycans in vivo remain poorly understood. In our study, we focused on elucidating these functions using Drosophila as a model system. Our experiments concentrated on analyses of phenotypes associated with defects in the protein O‐mannosyltransferase (POMT) genes, rotated abdomen (rt) and twisted (tw). We characterized temporal and cell‐specific requirements of POMT genes for normal neuromuscular physiology and proper body posture. Using a combination of genetic, immunofluorescent and live imaging approaches, we unveiled new phenotypes, including defects of embryonic body posture caused by uncoordinated muscle contractions. Our experiments indicated that POMT activity is simultaneously required in muscles and neurons, suggesting that POMT genes affect communication between these cells. We found that coordinated waves of muscle contractions induce rolling behavior, which also suggested an innate chirality of embryo ‐ shell interactions. Our data provided evidence that abnormal protein O‐mannosylation result in a defect of the sensory feedback that controls the pattern of muscle contractions. Our experiments also suggested that peripheral multidendritic neurons play an important role in the pathogenic mechanism of abnormal muscle contractions and the body rotation phenotype. Taken together, our results elucidated in vivo functions mediated by the POMT pathway in Drosophila, which could shed light on potential analogous mechanisms in mammals.Support or Funding InformationThis project was supported in part by NIH/NS075534