JAK-STAT signaling during CNS development

描述(申请人提供)：这项研究计划的长期目标是了解在哺乳动物中枢神经系统(CNS)发育过程中调节神经发生和胶质形成顺序发生的分子机制。我们和其他人最近发现，在神经发生期间，中枢神经系统前体细胞即使在强大的胶质诱导因子治疗下也无法分化为神经胶质细胞。这一观察结果使我们假设，在神经发生阶段，CNS前体细胞固有的细胞特性负向调节神经胶质分化因子，以防止早熟胶质发生，从而维持神经元和神经胶质分化的顺序开始。为了验证这一假说，我们将研究重点放在了LIF诱导的JAK-STAT通路这一主要星形胶质形成通路的调控上。这一途径在中枢神经系统星形胶质细胞分化中的关键作用体现在星形胶质细胞发生障碍的小鼠身上，该途径的不同组成部分被单基因敲除。我们的初步研究表明，在神经发生期间，JAK-STAT信号的激活和功能在培养的皮质祖细胞中受到抑制。在这项研究中，我们将进一步研究神经发生期间星形胶质细胞的缺乏是否是由于在活体皮质神经发生过程中JAK-STAT通路的抑制，以及STAT信号的激活改变是否导致星形胶质细胞发生的延迟或早熟。我们的研究将试图解决JAK-STAT通路的不同组成部分如何参与神经发生期间星形胶质形成信号的下调。我们还希望勾勒出更详细的时间进程和事件序列，用于该途径的各个组成部分的发育调节。总之，这项研究将有助于建立证据，证明星形胶质形成的JAK-STAT通路在皮质神经发生过程中确实受到抑制，这对于未来的机制研究将是重要的，以确定神经发生过程中胶质形成通路是如何被抑制的，以及当细胞变得胶质形成时如何克服这种抑制。对这些机制的全面了解最终将使我们能够更充分地了解细胞命运决定以及神经发生和胶质发生的顺序发生在发育中的中枢神经系统中是如何实现的。

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.