Regulation of hypothalamic radial glia by Wnt signaling

Wnt 信号传导调节下丘脑放射状胶质细胞

基本信息

批准号：
9020773
负责人：
RICHARD I DORSKY
金额：
$ 32.59万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9020773
关键词：
Ablation Address Adult Behavior Brain Brain Diseases Cells Data Development Embryo Embryonic Development Ensure Genes Genetic Goals Health Homeostasis Hypothalamic structure In Vitro Injury Laboratories Lead Life Link Mediating Mediator of activation protein Mitogens Modeling Molecular Molecular Genetics Molecular Target Natural regeneration Neuroglia Neuronal Differentiation Neurons Pathway interactions Phenotype Physiology Population Process Proliferating Public Health Radial Regenerative response Regulation Regulatory Pathway Reporter Role Signal Pathway Signal Transduction Staging Stem cells System Testing Tissues Transgenic Organisms Work Zebrafish adult neurogenesis genetic approach genetic manipulation in vivo mutant nerve stem cell neurogenesis novel progenitor repaired research study response self-renewal tissue regeneration tool transcriptome sequencing

项目摘要

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.

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具体调节途径知之甚少。脊椎动物大脑中的放射状胶质干细胞可以在稳态期间持续产生神经元，并在受伤后再生丢失的细胞。然而，人们对神经干细胞调节的分子机制知之甚少。我们实验室发现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。相比之下，斑马鱼下丘脑中放射状胶质细胞的形成不需要 Wnt 信号传导，并且异位 Wnt 活性会减少其数量。这项工作将测试 Wnt 信号传导将放射状胶质细胞转化为神经祖细胞并促进损伤后增殖反应的具体假设。首先，我们将确定 Wnt 信号传导对于驱动放射状胶质细胞进入神经祖细胞状态是否是必要和充分的。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，我们将确定损伤后放射状胶质细胞增殖是否需要 Wnt 信号传导。总之，这将表征脊椎动物下丘脑中新的神经祖细胞群的调节，并建立中枢神经系统神经发生中 Wnt 信号传导的新模型。