Regulation of hypothalamic radial glia by Wnt signaling

描述（由申请人提供）：调节成人神经发生和神经干细胞行为的特定调控途径尚不清楚。脊椎动物脑内的放射状胶质干细胞可以在稳态状态下持续产生神经元，并在损伤后再生失去的细胞。然而，神经干细胞调控的分子机制尚不清楚。我们的实验室已经发现Wnt信号通过转录效应物Lef1调控胚胎后斑马鱼下丘脑的神经发生。相反，斑马鱼下丘脑放射状胶质细胞的形成不需要Wnt信号，而异位的Wnt活性会减少它们的数量。这项工作将验证Wnt信号在将放射状胶质细胞转化为神经祖细胞并促进其损伤后增殖反应中的特定假设。首先，我们将确定Wnt信号是否必要和充分驱动放射状胶质细胞进入神经祖细胞状态。其次，我们将测试Lef1是否通过下游靶点促进神经祖细胞的形成。第三，我们将确定损伤后径向胶质细胞增殖是否需要Wnt信号。总之，这将表征脊椎动物下丘脑中一个新的神经祖细胞群体的调控，并建立一个新的Wnt信号传导在中枢神经系统神经发生中的模型。

DESCRIPTION (provided by applicant): The specific regulatory pathways regulating adult neurogenesis and the behavior of neural stem cells are poorly understood. Radial glial stem cells in the vertebrate brain can continuously produce neurons during homeostasis and regenerate lost cells following injury. Yet the molecular mechanisms underlying neural stem cell regulation are poorly understood. Our laboratory has discovered that Wnt signaling regulates neurogenesis in the post-embryonic zebrafish hypothalamus via the transcriptional effector Lef1. In contrast the formation of radial glia in the zebrafish hypothalamus does not require Wnt signaling and ectopic Wnt activity reduces their number. This work will test the specific hypotheses that Wnt signaling functions to convert radial glia into neural progenitors, and to promote their proliferative response following injury. First, we will determine whether Wnt signaling is necessary and sufficient to drive radial glia into a neural progenitor state. Second, we will test whether Lef1 promotes neural progenitor formation through downstream targets. Third, we will determine whether Wnt signaling is required for radial glial proliferation after injry. Together, this will characterize the regulation of a novel population of neural progenitors in the vertebrate hypothalamus, and establish a new model for Wnt signaling in CNS neurogenesis.