| dc.identifier.uri | http://hdl.handle.net/1951/56101 | |
| dc.identifier.uri | http://hdl.handle.net/11401/71678 | |
| 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 | |
| dc.format.medium | Electronic Resource | en_US |
| dc.language.iso | en_US | |
| dc.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dc.type | Dissertation | |
| dcterms.abstract | The myelin-producing oligodendrocytes of the central nervous system are critical to normal brain function and physiology. The molecular mechanisms that influence oligodendrocyte development and CNS myelination, however, remain poorly understood. One potential factor that may regulate these processes is the extracellular matrix (ECM) molecule laminin. Children with mutations in one type of laminin - the alpha 2 subunit (LAMA2) - have defects in the size and shape of the forebrain and cerebellum, along with white matter abnormalities. However, it is not clear whether laminin a2 modulates oligodendrocytes in vivo, and if so, through which cellular signaling pathways. In this dissertation, I used LAMA2-deficient dy/dy and LAMA2-knockout (dy3k/dy3k) mice to investigate the influence of laminin a2 on oligodendrogenesis, oligodendrocyte maturation, and CNS myelination. We found that laminin a2 regulates the organization and cellular composition of the postnatal subventricular zone (SVZ), a major gliogenic niche. Loss of LAMA2 resulted in abnormal oligodendrogenesis, such that initially LAMA2-knockout mice had fewer oligodendrocyte progenitor cells (OPCs) compared to their wildtype littermates. During the active myelination period, LAMA2-deficient brains were also found to have a developmental delay in oligodendrocyte maturation. These defects in OPC genesis and maturation correlated with axonal dysmyelination in various CNS white matter regions. We also identified several signaling abnormalities that may be contributing to these oligodendrocyte defects. LAMA2-deficient brains showed dysregulated Fyn (a Src Family Kinase known to regulate myelination) and elevated levels of C-terminal Src kinase (Csk) and Csk-binding-protein (Cbp), proteins that suppress Fyn activity. Laminin substrates were furthermore found to modulate Fyn regulation and to promote the transition of cultured oligodendrocyte progenitors to newly-formed oligodendrocytes in a Fyn-dependent manner. These findings indicate that the dysregulation of signaling pathways required for normal oligodendrocyte development may contribute to CNS abnormalities observed in congenital muscular dystrophy type 1A (MDC1A), and identify novel mechanisms by which laminins regulate oligodendrogenesis, oligodendrocyte lineage progression, and CNS myelination in the developing brain. | |
| dcterms.available | 2012-05-17T12:22:02Z | |
| dcterms.available | 2015-04-24T14:48:30Z | |
| dcterms.contributor | Holly A. Colognato. Joel M. Levine. | en_US |
| dcterms.contributor | Styliani-Anna E. Tsirka | en_US |
| dcterms.contributor | Gary G. Matthews | en_US |
| dcterms.contributor | William J. Brunken. | en_US |
| dcterms.creator | Relucio, Jenne Liza Villaranda | |
| dcterms.dateAccepted | 2012-05-17T12:22:02Z | |
| dcterms.dateAccepted | 2015-04-24T14:48:30Z | |
| dcterms.dateSubmitted | 2012-05-17T12:22:02Z | |
| dcterms.dateSubmitted | 2015-04-24T14:48:30Z | |
| dcterms.description | Department of Molecular and Cellular Biology | en_US |
| dcterms.format | Application/PDF | en_US |
| dcterms.format | Monograph | |
| dcterms.identifier | Relucio_grad.sunysb_0771E_10417.pdf | en_US |
| dcterms.identifier | http://hdl.handle.net/1951/56101 | |
| dcterms.identifier | http://hdl.handle.net/11401/71678 | |
| dcterms.issued | 2011-05-01 | |
| dcterms.language | en_US | |
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Previous issue date: 1 | en |
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Previous issue date: 1 | en |
| dcterms.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dcterms.subject | Cellular Biology -- Developmental Biology | |
| dcterms.subject | CNS, ECM, gliogenesis, laminin, myelin, oligodendrocyte | |
| dcterms.title | The Role of Laminin a2 in Oligodendrocyte Development and CNS Myelination | |
| dcterms.type | Dissertation | |
