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

FMRP 和 FXR1 在新皮质发育过程中神经干细胞中的作用

• 批准号: 8174535
• 负责人: Zhigang Xie
• 金额: $ 20.44万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8174535
• 关键词: Actins; Adult; Affect; Antibodies; Autistic Disorder; Brain; Cell Proliferation; Cell Therapy; Data; Databases; Defect; Development; Disease; Drosophila genus; Drug Delivery Systems; Electroporation; Embryo; Epilepsy; Exhibits; FMR1 Gene; FXR1 gene; FXR2 gene; Family member; Financial compensation; Fragile X Mental Retardation Protein; Fragile X Syndrome; Future; Gene Expression; Genetic; Goals; Homologous Gene; Human; Image; Inherited; Knock-out; Knockout Mice; Laboratory mice; Mediating; Mental Retardation; Molecular; Mus; Mutant Strains Mice; Myocardium; Neocortex; Neurons; Pathogenesis; Patients; Perinatal; Protein Family; Proteins; Role; Skeletal Muscle; Stem cells; Structure; Synapses; Testing; Tissues; Transcript; Ventricular; Wild Type Mouse; X Chromosome; base; effective therapy; in utero; knock-down; loss of function mutation; member; neocortical; nerve stem cell; novel; research study; small hairpin RNA

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.

描述（由申请人提供）：脆弱的X综合征（FXS）是最常见的遗传智障形式，也是自闭症和癫痫病的经常原因。该项目的长期目标是阐明FXS的基本机制，以此作为开发更有效治疗的先决条件。 FXS是由X染色体基因FMR1（脆弱的X智力低下1）中功能丧失突变引起的，该突变编码FMRP（脆弱的X智力低下蛋白）。在过去的二十年中，FMRP的研究集中在其突触发育中的功能上。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对于通过调节小鼠新皮质发育过程中的肌动蛋白动力学来维持NSC池很重要。由于NSC的异常可能导致产生的神经元的数量和/或类型不正确，因此脑功能受损，因此研究FMRP在NSC中的作用对于理解FXS的发病机理非常重要。该项目将检验以下假设：FMRP及其同源物之一FXR1在新皮层开发过程中起作用以维持NSC池。在特定的目标I中，将进行敲低和敲除分析，以确定FXR1的损失如何影响新皮层发育过程中NSC池和肌动蛋白动力学。在特定的目标II中，将跨越FMR1和FXR1突变小鼠，以评估FMRP和FXR1在调节新皮质发育过程中NSC池和肌动蛋白动力学方面的潜在冗余功能。该项目的成功完成将确定FMRP家族成员在新皮层开发过程中的作用，因此为FXS人类患者的潜在发展NSC缺陷提供了彻底分析的基础。发展性NSC缺陷将代表研究FXS的发病机理和治疗的新方向。此外，该项目的成功完成将提高FMRP家族的成员可能是操纵基于干细胞疗法中NSC增殖的新型药物目标的可能性。 公共卫生相关性：脆弱的X综合征（FXS）是最常见的智力智能遗传形式，也是自闭症和癫痫病的经常原因。了解FXS发病机理的基础机制是开发有效治疗的关键。该项目将确定FXS中是否涉及发育神经干细胞缺陷。