Functional mechanisms underlying Dystroglycan-dependent and independent roles of protein O-mannosylation in the nervous system
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abstract
The main objective of this project is to elucidate functional mechanisms underlying regulation of thenervous system by protein O-mannosylation (POM). POM is an essential type of O-glycosylation that has aprofound effect on the development and physiology in a broad range of animals, from Drosophila tohumans. Although the spectrum of biological functions affected by POM is wide, so far the only well-studiedtarget of POM is Dystroglycan (Dg). Defects in POM modifications of Dg result in severe musculardystrophies called dystroglycanopathies. Pathomechanisms associated with POM defects are complex andremain poorly understood, particularly in the nervous system. Recent studies suggested that POMmodification affects functions of many proteins, which contributes to pathogenic mechanisms ofdystroglycanopathies. However, functions of POM on proteins besides Dg are largely unknown. Thecomplexity of glycosylation and limitations of in vivo approaches create significant challenges for studyingPOM in mammalian organisms. Here we propose a multidisciplinary project that uses advantages ofDrosophila model, including powerful arsenal of genetic approaches, simplified glycosylation andexperimental amenability of POM and Dg mutants, to elucidate molecular and cellular mechanisms of Dg-dependent and Dg-independent functions of POM, with the focus on the nervous system andneuromuscular development and physiology. Our preliminary studies suggested that Receptor ProteinTyrosine Phosphatases (RPTPs) are functionally important POM targets and revealed that POM regulatescoordinated muscle contractions by affecting communication between sensory neurons and the CNS. Wewill capitalize on these results while focusing on three specific aims: (1) To analyze the role of POM inregulation of sensory neurons and coordinated muscle contractions. Using live imaging techniquescombined with genetic and neurobiological approaches, we will comprehensively investigate the role ofPOM in communication between sensory neurons, CNS cells and muscles. (2) To investigate the effect ofPOM on RPTP function. Using in vivo and in vitro approaches, we will investigate how POM affectsfunctions RPTPs at molecular, cellular, and organismal levels. (3) To reveal new molecular targets of POMand elucidate their function in the nervous system. We will use glycoproteomic approaches to identifyproteins with POM modifications. We will analyze functions of POM on novel targets in vivo, focusing onproteins that function in the nervous system. We anticipate that this project will establish new paradigms ofPOM-mediated regulation of the nervous system and will elucidate new evolutionarily conserved, Dg-dependent and independent mechanisms of POM functions, which will shed light on pathomechanisms ofhuman diseases associated with POM abnormalities.Â
