Molecular/genetic control of oligodendrocyte development

描述（由申请人提供）：本研究的长期目标是了解控制少突胶质细胞特化和分化的分子机制。虽然已经获得了相当多的见解，控制少突胶质细胞的初始规格的分子机制，它仍然不清楚如何在动物发育过程中的终末分化和髓鞘的少突胶质细胞的调节。最近，我们已经证明，少突胶质细胞祖细胞开始获得Nkx2.2同源结构域转录因子的表达，在其迁移到其目的地网站，和Nkx2.2的表达所需的少突胶质细胞分化和髓鞘基因的表达。在这里，我们假设Nkx2.2在控制动物发育过程中少突胶质细胞分化和髓鞘形成的时间方面起着关键作用，并且Nkx2.2的表达和活性受到细胞内和细胞外因子的密切调节。 该提案的具体目标1是检验Nkx2.2和Sox10物理相互作用并对激活髓鞘基因表达和少突胶质细胞分化具有协同作用的假设。具体目标2是检验Nkx2.2在少突胶质细胞祖细胞中的表达可以由促进少突胶质细胞分化的细胞外因子（甲状腺激素）诱导的假设。具体目标3是检验Notch途径通过调节少突胶质细胞祖细胞中Nkx2.2表达来控制少突胶质细胞分化的时间的假设。具体目标4是测试Nkx2.2与Nkx6.2合作在动物生命的后期调节少突胶质细胞髓鞘形成的假设。 这些研究结果将有助于我们进一步了解少突胶质细胞早期特化和分化的遗传通路，并可能为运动神经元和少突胶质细胞萎缩的防治提供新的治疗方法。

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.