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    Elucidating the Role of Plasticity-Related Gene Type 3 Protein in the Central Nervous System

    Cover for Elucidating the Role of Plasticity-Related Gene Type 3 Protein in the Central Nervous System
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    View/Open: AgbaegbuIweka_georgetown_0076D_14156.pdf (76.MB) Bookview

    Creator
    Agbaegbu Iweka, Chinyere Anne
    Advisor
    Geller, Herbert M
    Burns, Mark P
    ORCID
    https://orcid.org/0000-0001-9228-2436
    Abstract
    PRG-3 (Plasticity-Related Gene), a member of a family of lipid phosphatase related proteins, also known as Phospholipid Phosphatase-Related Protein Type (PLPPR) proteins, are integral membrane proteins characterized by six transmembrane domains. This family of proteins is enriched in the brain, and recent data indicate potential pleotropic functions in several different contexts. An inherent ability of this family of proteins is to promote the formation of membrane protrusions, and we have previously reported a cooperative function between the members of this family to induce membrane protrusions. PRG-3 was identified in a phospho-proteomic screen of proteins whose phosphorylation state was altered in response to Chondroitin Sulfate Proteoglycans (CSPGs), a robust inhibitor of axon growth. However, the function of PRG-3 is not yet understood. Here, we report that exogenous expression of PRG-3 increases cell adhesion to the ECM substrate resulting in decreased cell migration by altering cytoskeletal dynamics and modulating RhoA and Rac1 activity through association with RhoGDI, thus, enabling PRG-3 to overcome the inhibitory activity of CSPGs and LPA, another negative regulator of axon growth. We also show that deletion of PRG-3 resulted in the dilation of the lateral ventricles and increased dendritic spine density resulting in profound behavioral phenotypes. The PRG-3 knock-out mice exhibit general anxiety and hypoactivity, impaired prepulse inhibition and deficits in contextual learning and memory. Altogether, the data presented here suggest that PRG-3 may play a role in maintaining LPA levels in the brain parenchyma and may influence dendritic spine formation, maturation or pruning. Additionally, these results establish a novel signaling pathway for PRG-3 protein and by studying PRG-3 and its role in influencing cytoskeletal changes, we are reinforcing the significance of the factors and molecular mechanisms that govern axon growth after injury.
    Description
    Ph.D.
    Permanent Link
    http://hdl.handle.net/10822/1053076
    Date Published
    2018
    Subject
    CSPG; LPA; PLPPR; PRG-3; Rac1; RhoA; Neurosciences; Cytology; Neurosciences; Cellular biology;
    Type
    thesis
    Publisher
    Georgetown University
    Extent
    136 leaves
    Collections
    • Graduate Theses and Dissertations - Neuroscience
    Metadata
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    Georgetown University Seal
    ©2009 - 2022 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility