Role of CLASP2 in Neurodevelopment

描述（由申请人提供）：神经元迁移的中断导致严重的神经和发育障碍，如认知缺陷和癫痫，主要在儿科人群中得到认可。一个对神经元迁移和大脑发育至关重要的信号通路是由进化保守的糖蛋白Reelin启动的。Reelin通路中的人类突变产生的表型与细胞骨架蛋白突变引起的表型相似，这些突变破坏了微管和肌动蛋白的功能。这些儿童遗传研究的结果强烈表明，包括Reelin通路在内的几种信号通路聚集在下游细胞骨架蛋白上，影响适当的神经元迁移、大脑发育和认知。我们使用系统生物学方法鉴定了微管稳定CLASP2作为Reelin信号传导的关键细胞骨架修饰剂。我们之前发现CLASP2在体外神经元发育过程中调节几种重要的表型，包括高尔基形态、神经元分支、轴突规格和突触活性，这些表型也受Reelin信号传导调节。然而，关于CLASP2的作用及其与Reelin信号通路在发育中的作用知之甚少。因此，我们的目标是了解Reelin信号在神经元和大脑发育过程中如何调节clasp2介导的细胞骨架功能。在第一个目标中，我们将定义CLASP2与Reelin通路下游节点Dab1的相互作用，然后确定这种相互作用的功能后果。在第二个目标中，我们将确定CLASP2在大脑发育过程中的体内功能。提出的研究旨在促进对Reelin如何通过细胞骨架重组（正常大脑发育的关键要素）控制神经元迁移的理解。

DESCRIPTION (provided by applicant): 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.