Molecular/genetic control of oligodendrocyte development

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DESCRIPTION (provided by applicant): The long-term goal of this study is to understand the molecular mechanisms that control the specification and differentiation of oligodendrocytes. Although considerable insights have been gained into the molecular mechanisms that control the initial specification of oligodendrocytes, it is still not clear how the terminal differentiation and myelination of oligodendrocytes are regulated during animal development. Recently, we have demonstrated that oligodendrocyte progenitor cells start to acquire the expression of Nkx2.2 homeodomain transcription factor during their migration to their destination sites, and expression of Nkx2.2 is required for oligodendrocyte differentiation and myelin gene expression. Here we hypothesize that Nkx2.2 plays a key role in controlling the timing of oligodendrocyte differentiation and myelination during animal development, and the expression and activity of Nkx2.2 are tightly regulated by both intracellular and extracellular factors. Specific aim 1 of this proposal is to test the hypothesis that Nkx2.2 and Sox10 interact physically and have synergistic actions on activating myelin gene expression and oligodendrocyte differentiation. Specific aim 2 is to test the hypothesis that Nkx2.2 expression in oligodendrocyte progenitor cells can be induced by extracellular factors (thyroid hormone) that promote oligodendrocyte differentiation. Specific aim 3 is to test the hypothesis that the Notch pathway controls the timing of oligodendrocyte differentiation by regulating Nkx2.2 expression in oligodendrocyte progenitor cells. Specific aim 4 is to test the hypothesis that Nkx2.2 regulates oligodendrocyte myelination at later stages of animal life in collaboration with Nkx6.2. Results derived from the proposed studies will significantly enhance our understanding of the genetic circuitry governing the early specification and differentiation of oligodendrocytes, and may provide theoretic basis for design of novel therapeutic approaches for prevention and treatment of motor neuron and oligodendrocyte atrophies.