JAK-STAT signaling during CNS development

CNS 发育过程中的 JAK-STAT 信号传导

• 批准号: 7023773
• 负责人: YI EVE SUN
• 金额: $ 39.99万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7023773
• 关键词: DNA methylation; JAK kinase; biological signal transduction; cell differentiation; central nervous system; cerebral cortex; chromatin immunoprecipitation; developmental neurobiology; gel mobility shift assay; genetically modified animals; glia; laboratory mouse; laboratory rat; leukemia inhibitory factor; nerve stem cell; protein structure; receptor expression; transcription factor; western blottings

DESCRIPTION (provided by applicant): The long-range objective of this research proposal is to understand the molecular mechanisms that regulate the sequential onset of neurogenesis and gliogenesis during development of the mammalian central nervous system (CNS). We and others have recently found that CNS progenitor cells during the neurogenic period fail to differentiate into glia even when treated with potent glial-inducing factors. This observation led us to hypothesize that cellular properties intrinsic to CNS progenitors during the neurogenic phase negatively modulate glial differentiation factors in order to prevent precocious gliogenesis, thereby maintaining the sequential onset of neuronal and glial differentiation. To test this hypothesis we focused our studies on the regulation of one of the major astrogliogenic pathways, the LIF-induced JAK-STAT pathway. The crucial role of this pathway in CNS astrocyte differentiation is manifested by impaired astrogliogenesis in mice with single gene knockouts of various components of the pathway. Our preliminary studies suggest that activation and function of JAK-STAT signaling is inhibited in cultured cortical progenitors during the neurogenic period. In this study, we will further examine whether the lack of astrogliogenesis during the neurogenic period results from inhibition of the JAK-STAT pathway during cortical neurogenesis in vivo, and whether altered activation of STAT signaling leads to delayed or precocious onset of astrogliogenesis. Our studies will attempt to address how the various components of or related to the JAK-STAT pathway are involved in the downregulation of astrogliogenic signaling during the neurogenic period. We also hope to outline a more detailed time course and sequence of events for the developmental regulation of the various components of the pathway. In sum, this study will help to establish evidence that the astrogliogenic JAK-STAT pathway is indeed suppressed during cortical neurogenesis, which will be important for future mechanistic studies determining how gliogenic pathways are suppressed during neurogenesis and how this suppression is overcome when cells become gliogenic. A complete understanding of these mechanisms will eventually allow us to more fully understand how cell fate determination and the sequential onset of neurogenesis and gliogenesis is achieved in the developing CNS.

描述（由申请人提供）：该研究建议的远距离目标是了解调节在哺乳动物中枢神经系统（CNS）发展过程中神经发生和神经生成顺序发作的分子机制。 我们和其他人最近发现，即使用有效的神经胶质诱导因子治疗，神经源性时期的CNS祖细胞也无法分化为神经胶质。这一观察结果使我们假设在神经发生期间，CNS祖细胞固有的细胞性质对神经胶质分化因子进行负调节，以防止早熟的神经胶质发生，从而维持神经元和神经胶质分化的顺序发作。为了检验这一假设，我们将研究重点放在了主要的星形胶质生成途径之一，即LIF诱导的JAK-Stat途径上。该途径在CNS星形胶质细胞分化中的关键作用由小鼠中的星形胶质细胞生成受损，其单个基因敲除该途径的各个成分。我们的初步研究表明，在神经源时期，培养的皮质祖细胞中JAK-STAT信号的激活和功能受到抑制。在这项研究中，我们将进一步研究神经源性期间的星形胶质素发生是否是由于体内皮质神经发生过程中JAK-Stat途径的抑制是否导致的，以及Stat信号传导的激活改变是否会导致星形胶质形成的延迟或早体性发作。我们的研究将尝试解决与JAK-STAT途径的各种组成部分如何参与神经发生期间星形胶质成生物信号的下调。我们还希望概述更详细的时间课程和一系列事件，以概述该路径各个组成部分的发展调节。总而言之，这项研究将有助于建立证据，表明在皮质神经发生过程中确实抑制了星形胶质生成的JAK-STAT途径，这对于确定神经发生过程中神经胶质发生途径的未来机械研究非常重要，以及在细胞变得神经胶质发明时如何克服这种抑制。对这些机制的完整理解最终将使我们更充分地了解细胞命运的确定以及在发育中的CNS中如何实现神经发生和神经胶质发生的顺序发作。