Development and function of Crhbp+ neurons in the zebrafish hypothalamus

项目摘要/摘要 脊椎动物的下丘脑通过调节应激反应来维持生理平衡。 路径。这一途径的中断会导致神经精神障碍，但许多基因和神经元 涉案人员身份不明。我们的实验室已经发现Wnt通路介体Lef1调节下丘脑 神经发生和应激相关的探索行为，我的初步数据表明，特定的Lef1 在发育中的大脑中丰富的蛋白质亚型可能在这两种功能中都发挥着独特的作用。这个 表达促肾上腺皮质激素释放激素结合蛋白的下丘脑神经元的发育 依赖于Lef1及其转录靶点otbp，提供了一种假想的机制，将Wnt- 依赖于行为的转录。这项研究提案将检验这一假设，同时提供技术 和职业培训对于我成为一名独立的学术研究人员的目标是必不可少的。我的第一个目标是 生理和行为。在我的第二个目标中，我将使用细胞移植来创造基因嵌合体，以及 确定CrHBP+细胞是否必要且足以调节下游的探索行为 从这个项目中，我将确定斑马鱼之间可能保守的分子和电路 和人类压力反应途径，并获得新的技能，这将使我成为一名成功的科学家 也是导师。

Project Summary/Abstract The vertebrate hypothalamus maintains physiological homeostasis through regulation of the stress response pathway. Disruption of this pathway can lead to neuropsychiatric disorders, but many of the genes and neurons involved are unidentified. Our lab has discovered that the Wnt pathway mediator Lef1 regulates hypothalamic neurogenesis and stress-related exploratory behavior, and my preliminary data suggest that a specific Lef1 protein isoform enriched in the developing brain may play a unique role in both of these functions. The development of hypothalamic neurons expressing corticotropin-releasing hormone binding protein (Crhbp) depends on Lef1 as well as its transcriptional target otbp, providing a hypothesized mechanism linking Wnt- dependent transcription to behavior. This research proposal will test this hypothesis while providing technical and career training essential for my goal to become an independent academic researcher. In my first Aim I will create mutations disrupting specific Lef1 isoforms, and assess their effects on hypothalamic neurogenesis, physiology, and behavior. In my second Aim, I will use cell transplantation to create genetic chimeras, and determine whether Crhbp+ cells are necessary and sufficient to regulate exploratory behavior downstream of Lef1 and Otpb. From this project I will identify molecules and circuits that may be conserved between zebrafish and human stress response pathways, and gain new skills that will allow me to become a successful scientist and mentor.