Mechanisms of neural progenitor division in the developing brain

大脑发育中神经祖细胞分裂的机制

基本信息

批准号：
9285615
负责人：
Debra Silver
金额：
$ 34.34万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9285615
关键词：
Address Alleles Attention Autistic Disorder Award Binding Biological Biological Assay Brain Brain imaging Cell Fate Control Cell division Cells Cerebral cortex Chromosomes Complex Defect Development Developmental Process Diagnostic Dorsal Employee Strikes Etiology Exhibits Exons Funding Gene Expression Generations Genes Genetic Genetic Transcription Human Image In Vitro Investigation LIS1 protein Lesion 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 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 neuromechanism neuroregulation novel progenitor public health relevance self-renewal stem

Address Alleles Attention Autistic Disorder Award Binding Biological Biological Assay Brain Brain imaging Cell Fate Control Cell division Cells Cerebral cortex Chromosomes Complex Defect Development Developmental Process Diagnostic Dorsal Employee Strikes Etiology Exhibits Exons Funding Gene Expression Generations Genes Genetic Genetic Transcription Human Image In Vitro Investigation LIS1 protein Lesion 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 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 neuromechanism neuroregulation novel progenitor public health relevance self-renewal stem

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项目摘要

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基本发育过程。在发育中的脑皮质中，径向胶质细胞对称地分裂为自我更新和不对称，以产生神经元和其他祖细胞。我们缺乏对调节径向胶质分裂的细胞生物学机制的基本理解。此外，我们对径向胶质裂缝AR在分子水平上的定义（包括转录后调节的作用）有限有限。该提案的总体目的是阐明这些基本监管水平的贡献对于神经发生，通过利用新型小鼠神经发生突变体。该突变体对于MagOH来说是单倍型，这是外显子连接RNA结合复合物（EJC）的组成部分。我们以前由NIH资助的研究表明，MAGOH突变体表现出小头畸形，大脑比正常情况小30％，这主要是由于神经祖细胞降低。我们发现MAGOH对于适当的神经祖细胞的适当有丝分裂至关重要，并发现MAGOH调节Lis1（一种与微管相关的蛋白质对神经发生必不可少的蛋白质。此外，我们发现MAGOH控制关键神经祖细胞决定因素的表达。我们的发现共同指出了Magoh是神经发生的新型中心调节剂，但我们对MagoH在大脑中的功能缺乏基本的理解。我们提出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并在转录后调节模块中作用，该模块控制关键神经发生基因的表达。我们的中心假设是MAGOH通过影响有丝分裂的纺锤体和mRNA代谢来调节径向神经胶质的不对称分裂。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。我们将使用有条件的遗传分析，以及实时Brai切片中径向胶质分裂的实时成像。其次，我们将通过阐明其微管和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在有丝分裂中的下游功能。第三，我们将定义MAGOH在神经发生中的关键mRNA靶标，并确定EJC在调节中的作用。成功完成这些目标后，我们将通过调节有丝分裂和mRNA来大大提高对MAGOH如何影响神经发生的理解。总之，我们提出的研究将扩大我们对不对称分裂调节和神经发育障碍病因的基本理解。