Development and function of Crhbp+ neurons in the zebrafish hypothalamus

点击翻译按钮获取中文摘要

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.