Genetic Regulation of Neuronal Migration

神经元迁移的遗传调控

• 批准号: 7190485
• 负责人: ANTHONY J. WYNSHAW-BORIS
• 金额: $ 23.73万
• 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 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7190485
• 关键词: Address; Adult; Alanine; Bacteria; Binding; Binding Proteins; Biochemical Genetics; Biological; Brain; Cell Survival; Cells; Complex; Data; Defect; Development; Dynein ATPase; Embryo; Event; Family; Fibroblasts; Gene Proteins; Gene Transfer Techniques; Genes; Genetic; Homologous Gene; Homozygote; Human; LIS1 Pathway; Mitotic; Molecular; Motor; Mus; Mutant Strains Mice; Neurons; Pathway interactions; Phenotype; Phosphoproteins; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphorylation Site; Play; Process; Proteins; Publishing; Regulation; Research Personnel; Role; Serine; Signal Pathway; Somatic Cell; Staging; Testing; Threonine; Tissues; Transgenes; Transgenic Mice; Wild Type Mouse; base; dosage; homologous recombination; in vivo; member; migration; mouse model; mutant; neocortical; nerve stem cell; neuroblast; neurogenesis; programs

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，这些方法已经鉴定了新皮层发育和神经元迁移所需的几种基因和蛋白质产物。基于在小鼠模型中的遗传、生物化学和细胞生物学研究，这些基因和蛋白质产物中的许多已经被置于三个主要的功能通路中：CD 3 N通路、Cdk 5/p35通路和LIS 1通路。该项目的最新研究已经确定了这三种途径之间的一些重要串扰。然而，在我们的理解中有几个关键的差距。首先，尚不清楚这些通路和相互作用是否专门调节神经元迁移或参与大脑发育的其他过程，如神经发生和存活。其次，这些不同的成分和信号通路相互联系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。这是至关重要的，以确定整合的基因产物和它们的信号通路在神经元迁移的分子复杂性，管理新皮层的发展，更全面的了解。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LIS 1在体内神经发生、神经元迁移、细胞存活和成人神经元功能过程中的剂量依赖性作用，检验LIS 1在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，LIS 1是至关重要的过程中的所有阶段的大脑发育，甚至在有丝分裂后的成年人的大脑，虽然不是在非神经元体细胞组织。目的2通过BAG转基因小鼠体内产生特异性Cdk 5磷酸化位点突变体，验证Cdk 5/p35磷酸化NUDEL并与14-3- 3 β结合对神经元发育和迁移的重要性。目的3验证OCX是LIS 1通路的一部分的假设。基于我们的初步数据，我们预测，与LIS 1，OCX在动力蛋白运动功能的调节中发挥作用，并通过Cdk 5/p35磷酸化调节OCX活性可能类似于NUDEL调节。