Regulation of neural migration during brain development

这项研究将确定Cas衔接蛋白调节皮质神经元的机制。 发展和功能。准确的细胞迁移和层压对于细胞的发育是必不可少的。 功能性神经系统任何这些过程的先天性中断都可能导致神经发育障碍。 从无脑回畸形到自闭症谱系障碍。在多个发育阶段中， 神经元被排斥和吸引的线索引导，同时与细胞外基质积极相互作用 (ECM)和其他细胞。尽管我们对这些信号所需的配体-受体对了解很多， 调节细胞轨迹，仍然不知道如何整合和解释指导性和粘附性线索 在神经元内。已知胞质衔接蛋白的Cas（Crk相关底物）家族在细胞内传递信号。 下游的几个神经引导线索，并调节局灶性粘连营业额。使用Cas蛋白作为 模型，我们有一个独特的机会，以扩大我们的理解，如何指导和宽容的信号 在神经发育过程中，通路会聚以调节细胞粘附。为了验证卡斯 蛋白质是协调皮质层压和迁移所必需的，实验将组织成 三个具体目标。在强有力的初步数据的指导下，Cas基因的消融导致皮质 缺陷，类似鹅卵石无脑畸形，目标1将建立，第一次，功能 在皮质迁移和层压过程中Cas蛋白的需求。目标2将探讨 cas介导的皮质支架形成的生理和行为，使用脑电图和行为的方法。 目标3将测试Cas功能的调节如何影响皮质分层。这些实验将提供新的 关于建立感知所必需的神经回路的基本机制的知识 和认知。

The proposed studies will identify mechanisms through which Cas adaptor proteins regulate cortical development and function. Accurate cell migration and lamination are indispensable for the development of a functional nervous system. Congenital disruption of any of these processes can result in neurodevelopmental disorders ranging from lissencephaly to autism-spectrum disorders. During multiple developmental steps, neurons are guided by repulsive and attractive cues, while actively interacting with the extracellular matrix (ECM) and other cells. Although much is known about the ligand-receptor pairs required for these cues to regulate cell trajectories, it remains unknown how instructive and adhesive cues are integrated and interpreted within the neuron. The Cas (Crk associated substrate) family of cytosolic adaptor proteins are known to signal downstream of several neural guidance cues, and regulate focal adhesion turnover. Using Cas proteins as a model, we have a unique opportunity to broaden our understanding of how instructive and permissive signaling pathways converge during neural development to regulate cell adhesion. To test the hypothesis that Cas proteins are essential for coordinating cortical lamination and migration, experiments will be organized into three Specific Aims. Guided by strong preliminary data showing that ablation of Cas genes results in cortical defects that resemble cobblestone lissencephaly, Aim 1 will establish, for the first time, the functional requirement for Cas proteins during cortical migration and lamination. Aim 2 will explore the contributions of Cas-mediated cortical scaffold formation to physiology and behavior, using EEG and behavioral approaches. Aim 3 will test how regulation of Cas function affects cortical lamination. These experiments will provide new knowledge on the basic mechanisms underlying the establishment of neural circuits essential for perception and cognition.