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）是最常见的遗传性精神发育迟滞形式，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，作为开发更有效治疗方法的先决条件。FXS是由X染色体基因FMR 1（脆性X智力低下1）的功能缺失突变引起的，该基因编码FMRP（脆性X智力低下蛋白）。在过去的二十年里，FMRP的研究主要集中在其在突触发育中的功能。然而，最近的分析表明，FMRP在胚胎果蝇脑和成年小鼠脑中的神经干细胞（NSC）增殖中起关键作用。此外，我们的初步数据表明，FMRP是重要的维持神经干细胞池调节肌动蛋白动态在小鼠新皮层发育。由于神经干细胞的异常可能导致产生的神经元的数量和/或类型不正确，从而损害脑功能，因此研究FMRP在神经干细胞中的作用对于理解FXS的发病机制将是重要的。该项目将测试FMRP及其同源物之一FXR 1在新皮层发育期间冗余地维持NSC池的假设。在特定目标I中，将进行敲低和敲除分析，以确定FXR 1的缺失如何影响新皮层发育期间的NSC池和肌动蛋白动力学。在特异性目标II中，将使Fmr 1和Fxr 1突变小鼠杂交以评估FMRP和FXR 1在新皮质发育期间调节NSC池和肌动蛋白动力学的潜在冗余功能。该项目的成功完成将确立FMRP家族成员在新皮层发育期间在NSC中的作用，从而为在未来研究中彻底分析FXS人类患者中潜在的发育NSC缺陷提供基础。发育性神经干细胞缺陷将成为FXS发病机制和治疗研究的新方向。此外，该项目的成功完成将提高FMRP家族成员可能成为在基于干细胞的治疗中操纵NSC增殖的新型药物靶点的可能性。 公共卫生相关性：脆性X综合征（FXS）是最常见的遗传性精神发育迟滞，也是自闭症和癫痫的常见原因。了解FXS发病机制的基础是开发有效治疗方法的关键。该项目将确定发育神经干细胞缺陷是否参与FXS。

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.