Signal Transduction in Neuron Migration & Axon Guidance

人类大脑皮层的正常发育对认知功能至关重要，在智力迟钝和癫痫等人类神经系统疾病中受到破坏。我们和其他实验室的定位克隆工作已经确定了正常神经元迁移所需的几个基因，包括DCX、FLNA、ARFGEF2、Reelin、Dab1等。由于涉及轴突生长和神经元迁移的许多机制是共享的，因此其中一些基因也对轴突生长有影响。许多这些基因编码细胞质蛋白，这些蛋白通过与尚未很好定义的信号通路相互作用发挥作用。本提案的总体目标是分析Reelin/Dab1通路、双皮质素（Dcx）和双皮质素样激酶（Dclk）在神经元迁移和轴突生长中的作用。这两种途径似乎汇聚在微管的控制和神经元过程生长的调节上。具体目的1将分析Reelin/Dab1通路在控制神经元迁移的主导过程中的作用。具体目标2将分析Dclk在活动相关轴突生长和正常突触重塑中的作用。具体目的3将分析Dcx和Dclk在控制神经元向大脑皮层的正常迁移以及皮层轴突的正常生长和靶向中的相互作用：我们希望这项工作不仅能提高我们对它们正常作用的理解

Normal development of the human cerebral cortex is essential for cognitive function, and is disrupted in human neurological disorders such as mental retardation and epilepsy. Positional cloning efforts by our lab and others have identified several genes required for normal neuronal migration, including DCX, FLNA, ARFGEF2, Reelin, Dab1 and others. Since many of the mechanisms involved in axon outgrowth and neuronal migration are shared, some of these genes also have effects on axon outgrowth. Many of these genes encode cytoplasmic proteins that exert their effects via interactions with signaling pathways that are not yet well defined. The overall goal of this proposal is to analyze the role of the Reelin/Dab1 pathway, and of doublecortin (Dcx) and the doublecortin-like kinase (Dclk) in neuronal migration and axon outgrowth. These two pathways appear to converge on the control of microtubules and the regulation of process outgrowth in neurons. Specific aim 1 will analyze the role of the Reelin/Dab1 pathway in control of the leading process of migrating neurons. Specific aim 2 will analyze the role of Dclk in activity-related axon outgrowth and normal synaptic remodeling. Specific aim 3 will analyze the interacting roles of Dcx and Dclk in controlling the normal migration of neurons to the cerebral cortex, and the normal outgrowth and targeting of cortical axons: We hope that this work will not only improve out understanding of the normal role of these genes in cortical development but may also identify additional candidate genes for other human developmental disorders.