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    Role of protein O-mannosylation in nervous system development using Drosophila as a model

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    CHANDEL-DISSERTATION-2020.pdf (39.29Mb)
    Date
    2020-11-30
    Author
    Chandel, Ishita
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    Abstract
    Protein O-mannosylation (POM) is a post translational modification where enzymes add O-mannose to serine and threonine residues of proteins in the ER. Two well studied enzymes that work as a complex to add O-mannose sugar to Ser/Thr of proteins are protein –O-mannosyltransferase 1 and 2 (POMT1/2). Mutations in Pomt1/2 cause congenital muscular dystrophies (CMDs) in humans. Although substantial research has been done to elucidate the role of POMT1/2 in muscles, little is known about their role in neural development. In my dissertation, I used Drosophila as a model system to study the functions of POMT1/2 in nervous system development. Drosophila has orthologs of pomt1 and pomt2 called Rotated Abdomen (rt) and Twisted (tw), respectively. Mutations in rt and tw cause a clockwise rotation of abdominal segments in adult flies and embryos. I studied axon morphology of different types of sensory neurons which regulate muscle contraction, body position, pain and locomotion behavior in rt and tw mutants. I found that both genes are required to maintain axon connections of a class of multidendritic sensory neurons (Class IV) in the ventral nerve cord of Drosophila. Rescue results, RNAi experiments and mosaic analysis with a repressible cell marker (MARCM) revealed that the function of rt and tw in maintaining axon morphology is cell autonomous. I further studied the functionally relevant substrates of RT and TW. Dystroglycan (DG) is the only well-studied substrate of POMT1/2 in both humans and Drosophila. I found that Dystroglycan mutants do not fully recapitulate the defects seen in rt and tw mutants. This indicated the importance of other unknown substrates of RT and TW. To that end, I studied a group of transmembrane signal transduction proteins called receptor protein tyrosine phosphatases (RPTPs). Genetic interactions between tw and rptp mutants revealed synergistic roles in maintaining axon morphology. Mass spectrometry of the RPTP69D protein revealed that it is modified by RT and TW and co-overexpression of RT and TW adds extra O-mannose to RPTP69D. Further biochemical evidence revealed that O-mannose may protect RPTP69D from proteolysis. Overall, this research work established novel functions and novel substrates of POMT1/2, which might be evolutionarily conserved and shed light on the CMD mechanisms in humans.
    URI
    https://hdl.handle.net/1969.1/196493
    Subject
    O-mannosylation
    Nervous system
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    • Electronic Theses, Dissertations, and Records of Study (2002– )
    Citation
    Chandel, Ishita (2020). Role of protein O-mannosylation in nervous system development using Drosophila as a model. Doctoral dissertation, Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /196493.

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