Genetic Regulation of Neuronal Migration

神经元迁移的遗传调控

• 批准号: 7053406
• 负责人: ANTHONY J. WYNSHAW-BORIS
• 金额: $ 24.44万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7053406
• 关键词: artificial chromosomes; biological signal transduction; cell migration; cyclin dependent kinase; developmental neurobiology; dynein ATPase; gene mutation; genetic regulation; genetically modified animals; laboratory mouse; neocortex; nerve stem cell; neurogenesis

DESCRIPTION (provided by applicant): Recently our understanding of the molecular mechanisms governing the development of the brain has been facilitated by genetic approaches in human and mouse that have identified several genes and protein products required for neocortical development and neuronal migration. Many of these genes and protein products have been placed into three major functional pathways, based on genetic, biochemical and cell biological studies in mouse models: the RELN pathway, the Cdk5/p35 pathway and the LIS1 pathway. Recent studies from this program project have identified some important cross-talk between these three pathways. However, there are several critical gaps in our understanding. First, it is unknown if these pathways and interactions regulate exclusively neuronal migration or other processes involved in brain development such as neurogenesis and survival. Second, the manner and degree in which these various components and signaling pathways are interconnected are not known. Finally, the relationships of OCX to the three major pathways of neuronal migration are unknown. It is critical to determine the integration of the gene products and their signaling pathways during neuronal migration for a more comprehensive understanding of the molecular intricacies that govern neocortical development. Therefore, we propose to investigate the integration of these pathways by the following Specific Aims: Aim 1. Test the hypothesis that LIS1 has several important functions during brain development and in the adult by examining the dosage dependent effects of LIS1 during neurogenesis, neuronal migration, cell survival and adult neuronal function in vivo. Based on our published and preliminary data, we predict that LIS1 is critical for processes at all stages of brain development, and even in the postmitotic adult brain, although not in non-neuronal somatic tissues. Aim 2 Test the hypothesis that the phosphorylation of NUDEL by Cdk5/p35 and binding to 14-3-3epsilon are critical for neuronal development and migration in vivo by producing specific Cdk5 phosphorylation site mutants in mice by BAG transgenesis. Aim 3 Test the hypothesis that OCX is part of the LIS1 pathway. Based on our preliminary data, we predict that with LIS1, OCX plays a role in the regulation of dynein motor function, and that regulation of OCX activity via phosphorylation by Cdk5/p35 may be analogous to NUDEL regulation.

描述（由申请人提供）：最近，我们对控制大脑发育的分子机制的理解已经通过人类和小鼠的遗传方法得到了促进，这些方法已经确定了新皮层发育和神经元迁移所需的几个基因和蛋白质产物。基于小鼠模型的遗传、生化和细胞生物学研究，许多这些基因和蛋白产物被划分为三个主要的功能途径：RELN途径、Cdk5/p35途径和LIS1途径。该项目最近的研究发现，这三种通路之间存在一些重要的串扰。然而，在我们的理解中有几个关键的空白。首先，尚不清楚这些途径和相互作用是否只调节神经元迁移或其他涉及大脑发育的过程，如神经发生和生存。其次，这些不同成分和信号通路相互连接的方式和程度尚不清楚。最后，OCX与神经元迁移的三种主要途径的关系尚不清楚。确定神经元迁移过程中基因产物及其信号通路的整合对于更全面地了解控制新皮层发育的分子复杂性至关重要。因此，我们建议通过以下具体目的来研究这些途径的整合：目的1。通过在体内检测LIS1在神经发生、神经元迁移、细胞存活和成人神经元功能中的剂量依赖性作用，验证LIS1在大脑发育和成人中具有几种重要功能的假设。根据我们发表的和初步的数据，我们预测LIS1在大脑发育的所有阶段都是至关重要的，甚至在有丝分裂后的成人大脑中也是如此，尽管在非神经元体细胞组织中没有。目的2：通过BAG转基因在小鼠中产生特异性Cdk5磷酸化位点突变体，验证Cdk5/p35磷酸化NUDEL并结合14-3-3epsilon对神经元体内发育和迁移至关重要的假设。目的3验证OCX是LIS1通路一部分的假设。根据我们的初步数据，我们预测在LIS1中，OCX在动力蛋白运动功能的调节中发挥作用，并且通过Cdk5/p35磷酸化对OCX活性的调节可能类似于NUDEL调节。