Role of FMRP and FXR1 in neural stem cells during neocortical development

描述(申请人提供)：脆性X综合征(FXS)是最常见的遗传性智力低下形式，也是自闭症和癫痫的常见原因。该项目的长期目标是阐明FXS的潜在机制，作为开发更有效的治疗方法的先决条件。FXS是由编码脆性X智力低下蛋白(FMRP)的X染色体基因FMR1(脆性X智力低下1)功能缺失突变引起的。在过去的二十年里，对FMRP的研究主要集中在它在突触发育中的作用。然而，最近的分析揭示了FMRP在胚胎果蝇脑和成年小鼠脑中神经干细胞(NSC)增殖中的关键作用。此外，我们的初步数据表明，FMRP通过调节小鼠新皮质发育过程中的肌动蛋白动态，对于维持NSC池是重要的。由于神经干细胞的异常可能导致不正确的神经元数目和/或类型，从而损害脑功能，因此研究FMRP在神经干细胞中的作用对于了解FXS的发病机制具有重要意义。该项目将检验FMRP及其同源物之一FXR1在新皮质发育过程中冗余地维持NSC池的假设。在特定的目标I中，将进行基因敲除和基因敲除分析，以确定FXR1的缺失如何影响新皮质发育过程中的NSC池和肌动蛋白动态。在特定的目标II中，Fmr1和Fxr1突变小鼠将被杂交，以评估FMRP和FXR1在新皮质发育过程中调节NSC池和肌动蛋白动态的潜在冗余功能。该项目的成功完成将确立FMRP家族成员在神经干细胞在新皮质发育中的作用，从而为在未来的研究中深入分析FXS患者潜在的神经干细胞发育缺陷奠定基础。发育性神经干细胞缺陷将为研究FXS的发病机制和治疗提供新的方向。此外，该项目的成功完成将增加FMRP家族成员成为干细胞疗法中操纵NSC增殖的新药物靶点的可能性。 公共卫生相关性：脆性X综合征(FXS)是最常见的遗传性智力低下形式，也是自闭症和癫痫的常见原因。了解FXS的发病机制是开发有效治疗方法的关键。该项目将确定FXS是否与发育中的神经干细胞缺陷有关。

DESCRIPTION (provided by applicant): Fragile X syndrome (FXS) is the most common inherited form of mental retardation and a frequent cause of autism and epilepsy. The long term goal of this project is to elucidate the mechanisms underlying FXS as a prerequisite to the development of more effective treatments. FXS results from loss-of-function mutations in the X chromosome gene FMR1 (fragile X mental retardation 1), which encodes FMRP (fragile X mental retardation protein). Studies of FMRP in the past two decades have focused on its function in synaptic development. Recent analyses, however, have revealed a key role for FMRP in neural stem cell (NSC) proliferation in the embryonic Drosophila brain and in the adult mouse brain. Moreover, our preliminary data suggest that FMRP is important for maintaining the NSC pool by regulating actin dynamics during mouse neocortical development. Because abnormalities in NSCs may result in incorrect number and/or type of neurons produced and therefore impaired brain function, investigating the role of FMRP in NSCs will be important for understanding the pathogenesis of FXS. This project will test the hypothesis that FMRP and one of its homologs, FXR1, act redundantly to maintain the NSC pool during neocortical development. In Specific Aim I, knockdown and knockout analyses will be performed to determine how loss of FXR1 affects the NSC pool and actin dynamics during neocortical development. In Specific Aim II, Fmr1 and Fxr1 mutant mice will be crossed to assess potential redundant functions of FMRP and FXR1 in regulating the NSC pool and actin dynamics during neocortical development. Successful completion of this project will establish the role of the FMRP family members in NSCs during neocortical development, and therefore provide basis for thorough analysis of potential developmental NSC defects in FXS human patients in future studies. Developmental NSC defects will represent a new direction in studying the pathogenesis and therapy of FXS. In addition, successful completion of this project will raise the possibility that members of the FMRP family may be novel drug targets for manipulating NSC proliferation in stem cell-based therapies. PUBLIC HEALTH RELEVANCE: Fragile X syndrome (FXS) is the most common inherited form of mental retardation and also a frequent cause of autism and epilepsy. Understanding the mechanisms underlying the pathogenesis of FXS is the key to developing effective treatments. This project will determine whether developmental neural stem cell defects are involved in FXS.