Regulation of hypothalamic radial glia by Wnt signaling

描述（由申请人提供）：对调节成体神经发生和神经干细胞行为的特定调节途径知之甚少。脊椎动物脑中的放射状胶质干细胞可以在稳态期间连续产生神经元，并在损伤后再生丢失的细胞。然而，神经干细胞调控的分子机制知之甚少。我们的实验室已经发现Wnt信号通过转录效应子Lef1调节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，并且异位Wnt活性减少了它们的数量。这项工作将测试特定的假设，Wnt信号功能，以转换放射状胶质细胞成神经祖细胞，并促进其增殖反应损伤后。首先，我们将确定Wnt信号传导是否是必要的和足够的驱动径向神经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Wnt信号是否是损伤后放射状胶质细胞增殖所必需的。总之，这将表征脊椎动物下丘脑中神经祖细胞的新群体的调节，并建立CNS神经发生中Wnt信号传导的新模型。

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.