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规格和分化的分子机制。尽管人们对控制少突胶质细胞初始规格的分子机制有了相当多的了解，但仍不清楚动物发育过程中如何调节少突胶质细胞的终末分化和髓鞘形成。最近，我们证明少突胶质祖细胞在迁移到目的地过程中开始获得Nkx2.2同源域转录因子的表达，并且Nkx2.2的表达是少突胶质细胞分化和髓磷脂基因表达所必需的。在这里，我们假设Nkx2.2在动物发育过程中控制少突胶质细胞分化和髓鞘形成的时间中起着关键作用，并且Nkx2.2的表达和活性受到细胞内和细胞外因素的严格调控。 该提案的具体目标 1 是检验 Nkx2.2 和 Sox10 物理相互作用并在激活髓磷脂基因表达和少突胶质细胞分化方面具有协同作用的假设。具体目标2是检验以下假设：少突胶质细胞祖细胞中的Nkx2.2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。具体目标 3 是检验 Notch 通路通过调节少突胶质细胞祖细胞中 Nkx2.2 的表达来控制少突胶质细胞分化时间的假设。具体目标 4 是检验 Nkx2.2 与 Nkx6.2 合作在动物生命后期调节少突胶质细胞髓鞘形成的假设。 拟议研究的结果将显着增强我们对控制少突胶质细胞早期规范和分化的遗传回路的理解，并可能为设计预防和治疗运动神经元和少突胶质细胞萎缩的新治疗方法提供理论基础。

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.