Role of CLASP2 in Neurodevelopment

项目总结： 神经元迁移中断会导致严重的神经和发育障碍，如 认知缺陷和癫痫，主要在儿科人群中被认识到。一条信号通路 对于适当的神经元迁移和脑发育至关重要的是由进化保守的 糖蛋白Reelin。Reelin途径中的人类突变产生的表型与由 细胞骨架蛋白的突变，破坏微管和肌动蛋白的功能。这一切的高潮 对儿童的遗传学研究强烈表明，包括Reelin途径在内的几个信号通路 聚集在下游细胞骨架蛋白上，影响神经元的正常迁移、脑发育和 认知力。我们使用系统生物学的方法将稳定微管的CLASP2确定为关键 Reelin信号的细胞骨架修饰物。我们先前发现CLASP2调节几个重要的 神经元体外发育的表型包括高尔基体形态、神经元分支、轴突 规范和突触活性，表型也受Reelin信号调节。然而，几乎没有什么是 已知CLASP2的作用及其与发育中大脑中的Reelin信号通路的关联。 因此，我们的目标是了解Reelin信号如何调节CLASP2介导的细胞骨架功能 在神经元和大脑发育过程中。在第一个目标中，我们将定义CLASP2与Dab1、a 在Reelin途径的下游节点，然后确定这种相互作用的功能后果。 在第二个目标中，我们将定义CLASP2在脑发育过程中的体内功能。建议数 研究旨在促进对Reelin如何通过细胞骨架控制神经元迁移的理解 重组，正常大脑发育的关键要素。

PROJECT SUMMARY: Disruption in neuronal migration results in severe neurological and developmental impairments such as cognitive deficits and epilepsy that are recognized primarily in the pediatric population. A signaling pathway crucial for proper neuronal migration and brain development is initiated by the evolutionarily conserved glycoprotein Reelin. Human mutations in the Reelin pathway generate phenotypes that mimic those induced by mutations in cytoskeletal proteins that disrupt the function of microtubules and actin. The culmination of these genetic studies in children strongly suggests that several signaling pathways including the Reelin pathway converge on downstream cytoskeletal proteins to affect proper neuronal migration, brain development and cognition. We used a systems biology approach to identify the microtubule-stabilizing CLASP2 as a key cytoskeletal modifier of Reelin signaling. We previously found that CLASP2 regulates several important phenotypes during neuronal development in vitro including Golgi morphology, neuronal branching, axon specification and synaptic activity, phenotypes that are also regulated by Reelin signaling. However, little is known about the role of CLASP2 and its association with the Reelin signaling pathway in the developing brain. Therefore, our goal is to understand how Reelin signaling regulates CLASP2-mediated cytoskeletal function during neuronal and brain development. In the first aim, we will define the interaction of CLASP2 with Dab1, a downstream node in the Reelin pathway, and then determine the functional consequences of this interaction. In the second aim, we will define the in vivo function of CLASP2 during brain development. The proposed studies aim to advance the understanding of how Reelin controls neuronal migration through cytoskeleton reorganization, key elements of normal brain development.