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The Role of Dystroglycan in Differentiating Oligodendroglia and CNS Myelination

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dc.contributor.advisor Colognato, Holly en_US
dc.contributor.author Eyermann, Christopher Edward en_US
dc.contributor.other Department of Molecular and Cellular Pharmacology en_US
dc.date.accessioned 2013-05-24T16:38:14Z
dc.date.accessioned 2015-04-24T14:45:43Z
dc.date.available 2013-05-24T16:38:14Z
dc.date.available 2015-04-24T14:45:43Z
dc.date.issued 2012-12-01
dc.identifier.uri http://hdl.handle.net/1951/60214 en_US
dc.identifier.uri http://hdl.handle.net/11401/71049 en_US
dc.description 149 pg. en_US
dc.description.abstract During central nervous system (CNS) development, individual oligodendrocytes myelinate multiple axons, thus requiring the outgrowth and extensive branching of oligodendroglial processes. Extrinsic cues including the extracellular matrix (ECM) molecule laminin regulate oligodendrocyte maturation; indeed, laminin-deficient mice have fewer myelinated axons, which may indicate a defect in the ability to properly extend and branch processes. It remains unclear, however, to what extent ECM receptors contribute to oligodendroglial process remodeling itself. Here I report that the ECM receptor dystroglycan is necessary for laminin enhancement of filopodial formation, process outgrowth, and process branching in differentiating oligodendroglia. During early oligodendroglial differentiation, the disruption of dystroglycan-laminin interactions, via blocking antibodies or dystroglycan siRNA, resulted in decreased filopodial number and length, decreased process length, and decreased numbers of primary and secondary processes. Later in oligodendrocyte differentiation, dystroglycan-deficient cells developed fewer branches, thus producing less complex networks of processes as determined by Sholl analysis. In newly-differentiating oligodendroglia dystroglycan was localized in filopodial tips, while in more mature oligodendrocytes dystroglycan was enriched in FAK-positive focal adhesion structures. In addition to its role in promoting cytoskeletal reorganization, I have recently begun investigating a novel signaling role for dystroglycan in the nucleus. Our preliminary evidence suggests that dystroglycan localizes to the nucleus in oligodendrocyte progenitors (OPCs) and may play a role in dystroglycan-dependent modulation of oligodendroglial differentiation. Î -dystroglycan expression in the nuclear fraction of proliferating OPCs is higher than in differentiating oligodendrocytes; furthermore, I have detected an increased proportion of a cleaved form of Î -dystroglycan in the nucleus of proliferating OPCs relative to differentiated oligodendrocytes. Analysis of OPCs expressing a dystroglycan deletion construct reveal a preferential localization of the cytoplasmic domain of Î -dystroglycan to the nucleus, and decreased proliferation in response to growth factor stimulation. Our results suggest that dystroglycan may contribute to the overall myelinogenic capacity of individual oligodendroglia by influencing oligodendroglial process dynamics through dystroglycan-laminin interactions, and potentially modulating differentiation by signaling in the nucleus of oligodendroglial progenitors. en_US
dc.description.abstract During central nervous system (CNS) development, individual oligodendrocytes myelinate multiple axons, thus requiring the outgrowth and extensive branching of oligodendroglial processes. Extrinsic cues including the extracellular matrix (ECM) molecule laminin regulate oligodendrocyte maturation; indeed, laminin-deficient mice have fewer myelinated axons, which may indicate a defect in the ability to properly extend and branch processes. It remains unclear, however, to what extent ECM receptors contribute to oligodendroglial process remodeling itself. Here I report that the ECM receptor dystroglycan is necessary for laminin enhancement of filopodial formation, process outgrowth, and process branching in differentiating oligodendroglia. During early oligodendroglial differentiation, the disruption of dystroglycan-laminin interactions, via blocking antibodies or dystroglycan siRNA, resulted in decreased filopodial number and length, decreased process length, and decreased numbers of primary and secondary processes. Later in oligodendrocyte differentiation, dystroglycan-deficient cells developed fewer branches, thus producing less complex networks of processes as determined by Sholl analysis. In newly-differentiating oligodendroglia dystroglycan was localized in filopodial tips, while in more mature oligodendrocytes dystroglycan was enriched in FAK-positive focal adhesion structures. In addition to its role in promoting cytoskeletal reorganization, I have recently begun investigating a novel signaling role for dystroglycan in the nucleus. Our preliminary evidence suggests that dystroglycan localizes to the nucleus in oligodendrocyte progenitors (OPCs) and may play a role in dystroglycan-dependent modulation of oligodendroglial differentiation. Β-dystroglycan expression in the nuclear fraction of proliferating OPCs is higher than in differentiating oligodendrocytes; furthermore, I have detected an increased proportion of a cleaved form of Β-dystroglycan in the nucleus of proliferating OPCs relative to differentiated oligodendrocytes. Analysis of OPCs expressing a dystroglycan deletion construct reveal a preferential localization of the cytoplasmic domain of Β-dystroglycan to the nucleus, and decreased proliferation in response to growth factor stimulation. Our results suggest that dystroglycan may contribute to the overall myelinogenic capacity of individual oligodendroglia by influencing oligodendroglial process dynamics through dystroglycan-laminin interactions, and potentially modulating differentiation by signaling in the nucleus of oligodendroglial progenitors. en_US
dc.description.sponsorship This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. en_US
dc.format Monograph en_US
dc.format.medium Electronic Resource en_US
dc.language.iso en_US en_US
dc.publisher The Graduate School, Stony Brook University: Stony Brook, NY. en_US
dc.subject.lcsh Cellular biology--Neurosciences en_US
dc.subject.other Beta Dystroglycan, Dystroglycan, Nucleus, Oligodendrocyte, Process Branching, Process Outgrowth en_US
dc.title The Role of Dystroglycan in Differentiating Oligodendroglia and CNS Myelination en_US
dc.title The Role of Dystroglycan in Differentiating Oligodendroglia and CNS Myelination en_US
dc.type Dissertation en_US
dc.mimetype Application/PDF en_US
dc.contributor.committeemember Levine, Joel M en_US


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