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    Membrane Proteins Take Different Trafficking Pathways to the Primary Cilium

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    Authors
    Monis, William Joseph
    Faculty Advisor
    Gregory Pazour
    Academic Program
    Interdisciplinary Graduate Program
    UMass Chan Affiliations
    Program in Molecular Medicine
    Document Type
    Doctoral Dissertation
    Publication Date
    2017-12-14
    Keywords
    Membrane protein
    trafficking
    IFT20
    GMAP210
    exocyst
    BLOC-1
    fibrocystin
    polycystin-2
    smoothened
    cilia
    Cell Biology
    Developmental Biology
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    Abstract
    Cilia are conserved organelles that extend from the surface of most eukaryotic cells. During development cilia play key roles in force generation and perception of the extracellular environment. Ciliary defects cause a broad class of human diseases called ciliopathies characterized by pleiotropic symptoms including cystic kidneys, retinal degeneration, cardiac malformations and skeletal deformations. Perception of the environment relies on specific proteins being localized to the ciliary membrane compartment. The mechanism for sorting and trafficking membrane proteins to the cilium is poorly understood. To address this question, I developed a fluorescence-based pulse-chase assay to measure the transport kinetics of ciliary membrane proteins. This assay was used to determine the importance of candidate proteins to the delivery of fibrocystin, polycystin-2, and smoothened to cilia. Using this assay, I found that ciliary delivery of fibrocystin and polycystin-2 requires IFT20, GMAP210 and the exocyst while smoothened delivery is largely independent of these proteins. In addition, I determined that polycystin-2, but not smoothened or fibrocystin require the biogenesis of lysosome related organelles complex-1 (BLOC-1) for ciliary delivery. Consistent with a requirement for BLOC-1 in ciliary transport of polycystin-2, BLOC-1 mutant mice have cystic kidney disease. BLOC-1 functions in endosomal sorting and I find that disrupting the recycling endosome also reduced ciliary polycystin-2 and causes its accumulation in the recycling endosome. This is the first demonstration of a role for BLOC-1 in ciliary biogenesis and highlights the complexity of trafficking pathways to the cilium.
    DOI
    10.13028/M2GX0S
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/32330
    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/M2GX0S
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    Morningside Graduate School of Biomedical Sciences Dissertations and Theses

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