Recognition Molecules in Cortical Development

皮质发育中的识别分子

• 批准号: 7014058
• 负责人: Patricia F Maness
• 金额: $ 26.38万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7014058
• 关键词: axon; biological signal transduction; brain mapping; bromodeoxyuridine; cell communication molecule; cell migration; dendrites; fluorescent dye /probe; gene expression; gene mutation; genetically modified animals; glia; histology; integrins; laboratory mouse; mixed tissue /cell culture; neocortex; neural cell adhesion molecules; neurogenesis; neurogenetics; pyramidal cells; telencephalon; thalamocortical tract; video microscopy

DESCRIPTION (provided by applicant): CHL1 (Close Homolog of L1) is an integrin-interacting cell recognition molecule related to the L1 cell adhesion molecule with a potential role in area-specific development of the neocortex. Mutation of the CHL1 gene (CALL) in humans is associated with the 3p-syndrome of mental retardation. CHL1 is expressed in a high caudal to low rostral gradient in cortical precursors during radial migration and in differentiating pyramidal neurons. Preliminary results show CHL1 knockout mice exhibit area- and lamina-specific abnormalities in radial migration and apical dendrite projection of pyramidal cells, and topographic mapping errors of thalamocortical axons. The hypothesis to be tested is that CHL1 modulates radial migration of cortical neurons in the mouse neocortex with consequences on dendrite projection and thalamocortical mapping. Aims are: (1) To define the area- and lamina-specific distribution of cortical neurons and their dendritic development in homozygous and heterozygous CHL1 knockout mice and to assess the interaction of CHL1 with L1 in double mutant mice. A role for CHL1 in Semaphorin 3A-induced dendritic projection and branching of pyramidal neurons will be studied in cortical slices. (2) To determine the cellular mechanism of CHL1 in radial migration of cortical neurons in the posterior neocortex by BrdU labeling in vivo and in brain slice assays by time lapse videomicroscopy. (3) To investigate the molecular mechanism of CHL1 in intracellular signaling through intermediates (Src, Rac, Pak, ERK1,2) important for adhesion dynamics. (4) To identify topographic mapping defects in the thalamocortical projection of CHL1-/- mice by axon tracing in vivo and to analyze CHL1 function in thalamic axon guidance by axon tracing in embryos and a novel telencephalic whole mount assay. This investigation can reveal new molecular determinants and novel mechanisms governing cortical area development and provide insight into the pathology associated with mental retardation.

描述（由申请人提供）：CHL1（L1的亲密同源物）是与L1细胞粘附分子相关的整联蛋白相互作用识别分子，在新皮层的区域特异性发展中具有潜在的作用。人类中CHL1基因（CALL）的突变与智力低下的3P合成有关。 CHL1在径向迁移和分化金字塔神经元的皮质前体中高尾部的高尾梯度中表达。初步结果表明，CHL1敲除小鼠在radial骨迁移和锥体细胞的顶端树突投射中表现出面积和椎板特异性异常，以及丘脑皮质轴突的地形映射误差。 要检验的假设是，CHL1调节小鼠新皮层中皮质神经元的径向迁移，对树突投射和丘脑皮层映射的影响。目的是：（1）定义皮质神经元的面积和椎板特异性分布及其在纯合子和杂合CHL1敲除小鼠中的树突状发育，并评估CHL1与L1在双突变小鼠中的相互作用。 CHL1在Semaphorin 3a诱导的树突投射和锥体神经元的分支中的作用将在皮质切片中进行研究。 （2）通过在体内和脑部片段视频镜检查中，通过体内和脑切片测定中的BRDU标记在新皮层中皮质神经元的径向迁移中CHL1的细胞机制。 （3）通过中间体（SRC，RAC，PAK，ERK1,2）研究CHL1在细胞内信号传导中的分子机制。 （4）通过轴突在体内跟踪CHL1 - / - 小鼠的丘脑皮质投影中的地形图映射缺陷，并通过轴突跟踪胚胎在胚胎中和新型的远程脑脑化整体测定法中分析丘脑轴突指导中的CHL1功能。 这项研究可以揭示有关皮质区域发展的新分子决定因素和新型机制，并提供了与智力低下相关的病理学的见解。