Non-Radial Cell Migration in CNS Development

细胞迁移是中枢神经系统（CNS）正常发育的基础，这一过程中的扰动与许多神经系统疾病的发病机制有关，包括癫痫、智力迟钝和自闭症。了解这些常见疾病的发病机制，除其他过程外，还需要阐明控制神经元迁移的分子和细胞机制。在大脑皮层发育过程中，细胞迁移有两种主要途径：放射状和非放射状。至少在啮齿类动物中，细胞径向迁移，从苍白侧脑室区到皮层板，产生了大脑皮层的投射神经元，而皮层中间神经元必须沿着非径向路径从苍白下增殖区到达皮层板。在过去的五年里，在这项资助的支持下，我们对神经元间迁移的理解做出了重大贡献。在接下来的两年里，我们计划扩展这些研究，以更清楚地定义哺乳动物非径向细胞迁移的机制。一个基本问题是，引导过程如何响应引导信号，引导中间神经元从神经节隆起沿其迂回路径迁移，最终进入大脑皮层。我们假设，前导过程的功能就像生长锥一样，根据长、短的信号动态调节其细胞骨架。在此，我们建议定义迁移前导过程中的细胞骨架动力学，并确定它们如何受到引导线索的调节（目的1），并确定Lis1如何影响前导过程动力学（目的2）。这些数据将共同建立细胞机制，通过该机制，引导过程能够引导中间神经元的迁移，中间神经元是正常大脑发育的一个组成部分，在许多神经系统疾病中被破坏。

Cell migration is fundamental to normal central nervous system (CNS) development and perturbations in this process have been implicated in the pathogenesis of many neurologic disorders including epilepsy, mental retardation and autism. Understanding the pathogenesis of these all to common disorders requires, among other processes, the elucidation of the molecular and cellular mechanisms governing neuronal migration. Two primary pathways of cell migration are recognized during cerebral cortical development, radial and non-radial. At least in rodents, radial cell migration, from the pallial ventricular zone out to the cortical plate, gives rise to the projection neurons of the cerebral cortex, whereas cortical interneurons must travel along non-radial pathways from the subpallial proliferative zones to arrive in the cortical plate. Over the past five years, supported by this grant, we have made significant contributions to our understanding of interneuron migration. Over the next two years we plan to extend these studies to more clearly define the mechanisms governing non-radial cell migration in mammals. One fundamental questions is how does the leading process respond to guidance cues to direct the migrating interneurons from the ganglionic eminence along their circuitous path and finally into the cerebral cortex. We have hypothesis that the leading process functions like a growth cone by dynamically regulating its cytoskeleton in response to long and shortrange cues. Herein we propose to define the cytoskeletal dynamics in the migrating leading processes and establish how they are regulated by guidance cues (aim 1) and determine how Lis1 effects leading process dynamics (aim 2). Together these data will establish the cellular mechanisms by which the leading process is able to lead the migrating interneuron, an integral component of normal brain development and one that is disrupted in many neurologic disorders.