Genetic Regulation of Neuronal Migration

神经元迁移的遗传调控

• 批准号: 6929381
• 负责人: ANTHONY J. WYNSHAW-BORIS
• 金额: $ 25万
• 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/6929381
• 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，我们对人类和小鼠的遗传方法促进了对控制大脑发育的分子机制的理解，这些方法已经鉴定出新皮质发育和神经元迁移所需的几种基因和蛋白质产物。根据小鼠模型中的遗传、生化和细胞生物学研究，许多这些基因和蛋白质产物已被置于三个主要功能途径中：RELN 途径、Cdk5/p35 途径和 LIS1 途径。该计划项目的最新研究已经确定了这三种途径之间的一些重要的相互影响。然而，我们的理解存在一些关键差距。首先，尚不清楚这些途径和相互作用是否专门调节神经元迁移或涉及大脑发育的其他过程，例如神经发生和存活。其次，这些不同的成分和信号传导途径相互关联的方式和程度尚不清楚。最后，OCX 与神经元迁移的三个主要途径的关系尚不清楚。为了更全面地了解控制新皮质发育的分子复杂性，确定神经元迁移过程中基因产物及其信号通路的整合至关重要。因此，我们建议通过以下具体目标来研究这些途径的整合： 目标 1. 通过检查 LIS1 在神经发生、神经元迁移、体内细胞存活和成体神经元功能。根据我们已发表的初步数据，我们预测 LIS1 对于大脑发育的所有阶段的过程都至关重要，甚至在有丝分裂后的成人大脑中也至关重要，尽管在非神经元体细胞组织中并非如此。目标 2 通过 BAG 转基因在小鼠中产生特定的 Cdk5 磷酸化位点突变体，测试 Cdk5/p35 磷酸化 NUDEL 并与 14-3-3epsilon 结合对于体内神经元发育和迁移至关重要的假设。目标 3 检验 OCX 是 LIS1 通路一部分的假设。根据我们的初步数据，我们预测 OCX 通过 LIS1 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。