Motor Proteins in Brain Development

大脑发育中的运动蛋白

基本信息

批准号：
8410076
负责人：
Richard Bert Vallee
金额：
$ 31.18万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-08-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8410076
关键词：
Address Affect Apical Behavior Brain Cell Cycle Cell Cycle Progression Cell Cycle Regulation Cell Cycle Stage Cell Proliferation Cell division Cell model Cells Cellular Morphology Centrosome Chromatin Complement Complex Cytoskeletal Modeling Defect Development Disease Dynein ATPase Embryo Etiology Gene Proteins Genes Genetic Models Goals Grant Image In Vitro Kinesin Life Microcephaly Microtubules Modeling Molecular Molecular Models Morphogenesis Motor Mutate Mutation Neuroepithelial Neuroglia Neurons Nuclear Nuclear Envelope Pathway interactions Phosphorylation Site Phosphotransferases Play Process Production Protein Kinase Protein Kinase Inhibitors Proteins RNA Interference Radial Reagent Recruitment Activity Regulation Role Series Site Staging Stem cells Structure Testing Work adult stem cell base brain size brain tissue cell behavior inhibitor/antagonist interest lissencephaly migration molecular modeling neocortical neoplastic nerve stem cell neurogenesis new therapeutic target novel nucleocytoplasmic transport progenitor protein kinase inhibitor role model small molecule stem cell population

项目摘要

DESCRIPTION (provided by applicant): Defects in neocortical neurogenesis and migration cause severe brain developmental disease. LIS1, mutations in which cause lissencephaly (smooth brain), was the first neuronal migration gene to be identified. LIS1 functions in the cytoplasmic dynein pathway, indicating that microtubule motor proteins play a role in brain development. In earlier work supported by this grant we identified multiple discrete LIS1- and dynein- requiring stages in neurogenesis and migration, leading to a comprehensive model for the cellular basis of classical (type I) lissencephaly. We also found LIS1 to be required for the long-mysterious cell-cycle- dependent interkinetic nuclear migration (INM), a general feature of neuroepithelial and radial glial progenitor cell (RGPC) behavior. We have determined further that INM requires the activity of opposite-directed microtubule motor proteins, the plus end-directed unconventional kinesin Kif1a and cytoplasmic dynein. This model appears to explain the underlying mechanism for INM, and should allow us to address further basic and long-standing questions regarding its function and purpose. The Specific Aims are to determine the mechanism of nuclear transport by Kif1a; to determine how specific inhibition of basal and apical INM affect cell cycle progression and cell fate; and to determine the mechanisms for cell cycle control of INM using small molecule protein kinase inhibitors and other reagents. These issues have important implications for understanding how brain size, composition, and organization are controlled, and how stem cell proliferation is regulated under normal or neoplastic conditions. The analysis of genes responsible for INM and the use of small molecule cell cycle inhibitors will also identify potential targets for modulating neurogenesis and migration during early brain development.

描述（由申请人提供）：新皮质神经发生和迁移的缺陷会导致严重的脑发育疾病。 LIS1是引起lissencephaly（光滑脑）的突变，是第一个鉴定出的神经元迁移基因。 LIS1在细胞质动力蛋白途径中起作用，表明微管运动蛋白在大脑发育中起作用。在这笔赠款支持的早期工作中，我们确定了多个离散的LIS1和动力蛋白，需要在神经发生和迁移中进行阶段，从而为经典（I型）Lissencephaly的细胞基础提供了全面的模型。我们还发现，长期存在的细胞周期依赖性核迁移（INM）是必需的LIS1，这是神经上皮和径向神经胶质祖细胞（RGPC）行为的一般特征。我们进一步确定了INM需要相反的微管运动蛋白，加上终端定向的非常规驱动蛋白KIF1A和细胞质动力蛋白的活性。该模型似乎可以解释INM的基本机制，并应使我们能够解决有关其功能和目的的进一步和长期存在的问题。具体的目的是确定KIF1A核运输的机制；确定基础和顶端INM的特异性抑制如何影响细胞周期的进程和细胞命运；并使用小分子蛋白激酶抑制剂和其他试剂确定INM细胞周期控制的机制。这些问题对了解如何控制大脑的大小，组成和组织具有重要意义，以及如何在正常或肿瘤条件下调节干细胞增殖。负责INM的基因和使用小分子细胞周期抑制剂的分析还将确定在早期大脑发育过程中调节神经发生和迁移的潜在靶标。