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）：脆性 X 综合征 (FXS) 是最常见的遗传性智力障碍，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 X 染色体基因 FMR1（脆性 X 智力低下 1）功能丧失突变的结果，该基因编码 FMRP（脆性 X 智力低下蛋白）。过去二十年对 FMRP 的研究主要集中在其在突触发育中的功能。然而，最近的分析揭示了 FMRP 在胚胎果蝇大脑和成年小鼠大脑中神经干细胞 (NSC) 增殖中的关键作用。此外，我们的初步数据表明，FMRP 通过在小鼠新皮质发育过程中调节肌动蛋白动态，对于维持 NSC 池非常重要。由于 NSC 异常可能导致产生的神经元数量和/或类型不正确，从而损害大脑功能，因此研究 FMRP 在 NSC 中的作用对于了解 FXS 的发病机制非常重要。该项目将测试以下假设：FMRP 及其同源物之一 FXR1 在新皮质发育过程中发挥冗余作用以维持 NSC 库。在特定目标 I 中，将进行敲除和敲除分析，以确定 FXR1 的丢失如何影响新皮质发育过程中的 NSC 库和肌动蛋白动态。在 Specific Aim II 中，Fmr1 和 Fxr1 突变小鼠将进行杂交，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 家族成员在新皮质发育过程中 NSC 中的作用，从而为未来研究中 FXS 人类患者潜在发育 NSC 缺陷的全面分析提供基础。发育性 NSC 缺陷将代表研究 FXS 发病机制和治疗的新方向。此外，该项目的成功完成将提高FMRP家族成员可能成为干细胞疗法中操纵NSC增殖的新药物靶点的可能性。 公众健康相关性：脆性 X 综合征 (FXS) 是最常见的遗传性智力障碍，也是自闭症和癫痫的常见原因。了解 FXS 发病机制是开发有效治疗方法的关键。该项目将确定 FXS 是否涉及发育神经干细胞缺陷。