Mechanisms of neural progenitor division in the developing brain

大脑发育中神经祖细胞分裂的机制

• 批准号: 8665501
• 负责人: Debra Silver
• 金额: $ 34万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8665501
• 关键词: Address; Alleles; Attention; Autistic Disorder; Award; Binding; Biological; Biological Assay; Brain; Brain imaging; Cell division; Cells; Cerebral cortex; Chromosomes; Complex; Defect; Development; Developmental Process; Diagnostic; Dorsal; Employee Strikes; Etiology; Exhibits; Exons; Funding; Generations; Genes; Genetic; Human; Image; In Vitro; Investigation; Lesion; Life; Mechanics; Mediating; Mental disorders; Messenger RNA; Metabolism; Microcephaly; Microtubule-Associated Proteins; Microtubules; Mitosis; Mitotic; Mitotic spindle; Molecular; Molecular Probes; Mus; Mutation; National Institute of Neurological Disorders and Stroke; Nature; Neurodevelopmental Disorder; Neuroglia; Neurons; Phenotype; Positioning Attribute; Post-Transcriptional Regulation; Process; Production; Proteins; RNA; RNA Binding; Radial; Regulation; Role; Signal Pathway; Slice; Telencephalon; Testing; Therapeutic; Translations; United States National Institutes of Health; blind; brain malformation; cell fate specification; clinically relevant; genetic analysis; in vivo; mRNA Expression; mutant; nerve stem cell; neurogenesis; novel; progenitor; public health relevance; self-renewal; stem

DESCRIPTION (provided by applicant): Neurogenesis is an essential developmental process in which neural progenitors generate neurons. In the developing cerebral cortex, radial glia cells divide symmetrically to self-renew and asymmetrically to generate neurons and other progenitors. We lack a fundamental understanding of the cell biological mechanisms regulating radial glia divisions. In addition, we have a limited understanding of how radial glia divisions ar defined at the molecular level, including the role of post-transcriptional regulation. The overall objective of this proposal is to elucidate the contribution of these essential levels of regulation for neurogenesis, by exploiting a novel mouse neurogenesis mutant. This mutant is haploin-sufficient for Magoh, which is a component of the exon junction RNA binding complex (EJC). Our previous NIH-funded studies demonstrated that Magoh mutants exhibit microcephaly, with brains 30% smaller than normal, largely due to reduced neural progenitors. We found that Magoh is essential for proper mitosis of neural progenitors and discovered that Magoh regulates Lis1, a microtubule-associated protein essential for neurogenesis. Moreover we have found that Magoh controls expression of key neural progenitor determinants. Together, our discoveries point to Magoh as a novel central regulator of neurogenesis, yet we lack a fundamental understanding of how Magoh functions in the brain. We propose Magoh has two critical functions in neural progenitors: to regulate proper mitosis and to act in a post-transcriptional regulatory module controlling expression of key neurogenesis genes. Our central hypothesis is that Magoh regulates asymmetric division of radial glia by influencing the mitotic spindle and mRNA metabolism. To address this hypothesis we will pursue the following aims: First we will determine the cellular mechanism by which Magoh regulates neuron and INP production. We will use conditional genetic analysis along with live imaging of radial glia divisions in live brai slices. Second we will define how Magoh regulates mitosis by elucidating its regulation of microtubules and Lis1. We will determine how Magoh regulates Lis1 levels and if Lis1 functions downstream of Magoh in mitosis. Third, we will define the key mRNA targets of Magoh in neurogenesis and determine the role of the EJC in their regulation. Upon successful completion of these aims, we will have significantly advanced our understanding of how Magoh influences neurogenesis, by regulating both mitosis and mRNAs. Together, our proposed studies will broaden our fundamental understanding of the regulation of asymmetric division and the etiology of neurodevelopmental disorders.

描述（由申请人提供）：神经发生是神经祖细胞产生神经元的重要发育过程。在发育中的大脑皮层中，放射状胶质细胞对称分裂以自我更新，不对称分裂以产生神经元和其他祖细胞。我们对调节放射状胶质细胞分裂的细胞生物学机制缺乏基本的了解。此外，我们对如何在分子水平上定义放射状胶质细胞分裂，包括转录后调节的作用，了解有限。该提案的总体目标是阐明这些基本监管级别的贡献 通过利用一种新型的小鼠神经发生突变体来进行神经发生。该突变体对于 Magoh 来说是单倍体充足的，Magoh 是外显子连接 RNA 结合复合物 (EJC) 的一个组成部分。我们之前 NIH 资助的研究表明，Magoh 突变体表现出小头畸形，大脑比正常人小 30%，这主要是由于神经祖细胞减少。我们发现 Magoh 对于神经祖细胞的正常有丝分裂至关重要，并发现 Magoh 调节 Lis1（一种对神经发生至关重要的微管相关蛋白）。此外，我们发现 Magoh 控制关键神经祖细胞决定簇的表达。总之，我们的发现表明 Magoh 是神经发生的一种新型中枢调节剂，但我们对 Magoh 在大脑中如何发挥作用缺乏基本的了解。我们认为 Magoh 在神经祖细胞中具有两个关键功能：调节适当的有丝分裂和在控制关键神经发生基因表达的转录后调节模块中发挥作用。我们的中心假设是 Magoh 通过影响有丝分裂纺锤体和 mRNA 代谢来调节放射状胶质细胞的不对称分裂。为了解决这一假设，我们将追求以下目标：首先，我们将确定 Magoh 调节神经元和 INP 产生的细胞机制。我们将使用条件遗传分析以及活体 Brai 切片中径向胶质细胞分裂的实时成像。其次，我们将通过阐明 Magoh 对微管和 Lis1 的调节来定义 Magoh 如何调节有丝分裂。我们将确定 Magoh 如何调节 Lis1 水平以及 Lis1 是否在有丝分裂中的 Magoh 下游发挥作用。第三，我们将定义 Magoh 在神经发生中的关键 mRNA 靶标，并确定 EJC 在其调节中的作用。成功完成这些目标后，我们将显着加深对 Magoh 如何通过调节有丝分裂和 mRNA 影响神经发生的理解。总之，我们提出的研究将拓宽我们对不对称分裂调节和神经发育障碍病因学的基本理解。