Myelin-producing oligodendrocytes play crucial roles in supporting development and neuronal function of the mammalian central nervous system (CNS). Multiple sclerosis, a devastating disease of the CNS is triggered directly or indirectly by the failure of oligodendrocyte remyelination and the degeneration of mature oligodendrocytes. Despite the enormous clinical impact of this demyelinating disease, the biological mechanisms that initiate myelinogenesis and those that cause this disease state are not well understood. In a previous screen for genes required for glial cell development, I cloned and characterized a pair of oligodendrocyte lineage genes (Olig1/2) that encode a novel class of basic helix-loop-helix transcription factors. The Olig1 gene is expressed in oligodendrocyte progenitor cells and mature oligodendrocytes in rodents. Olig2 is essential for the formation of oligodendrocytes and motor neurons in the developing spinal cord. Gain-of-function and loss-of-function genetic studies show that Olig2 gene is critical for mediating oligodendrocyte development. The research proposal described here builds upon these preliminary studies. I will use in vivo conditional mutagenesis approaches to dissect the biological and pathological functions of the Olig2 gene in oligodendrocyte myelination and remyelination in an injury-induced demyelinating animal model. These studies should contribute significantly to our understanding of the molecular mechanisms of oligodendrocyte myelination and remyelination, and will offer new avenues for diagnosis and treatment of demyelinating diseases such as multiple sclerosis.
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