JAK-STAT signaling during CNS development

描述（由申请人提供）：本研究计划的长期目标是了解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发生顺序的分子机制。我们和其他人最近发现，在神经发生期的中枢神经系统祖细胞即使被有效的神经胶质诱导因子处理也不能分化为神经胶质细胞。这一观察结果使我们假设中枢神经系统祖细胞内在的细胞特性在神经发生阶段负向调节胶质细胞分化因子，以防止胶质细胞过早发生，从而维持神经元和胶质细胞分化的顺序发生。为了验证这一假设，我们将研究重点放在了主要的星形胶质细胞形成通路之一的调控上，即liff诱导的JAK-STAT通路。该通路在中枢神经系统星形胶质细胞分化中的关键作用表现为，该通路多种组分的单基因敲除使小鼠的星形胶质细胞形成受损。我们的初步研究表明，在培养的皮质祖细胞中，JAK-STAT信号的激活和功能在神经原性期受到抑制。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形成的缺乏是否源于体内皮层神经发生过程中JAK-STAT通路的抑制，以及STAT信号激活的改变是否导致星形胶质细胞形成的延迟或提前发生。我们的研究将试图解决JAK-STAT通路的各种成分或相关成分如何参与神经发生期星形胶质细胞生成信号的下调。我们还希望勾勒出更详细的时间过程和事件序列，以了解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，证明星形胶质源性JAK-STAT通路在皮层神经发生过程中确实受到抑制，这对于未来确定神经发生过程中胶质源性通路是如何被抑制的机制研究以及当细胞成为胶质源性时这种抑制是如何被克服的至关重要。对这些机制的完整理解最终将使我们能够更充分地了解细胞命运的决定以及神经发生和胶质瘤发生的顺序发生是如何在发育中的中枢神经系统中实现的。

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.