Role of CLASP2 in Neurodevelopment

描述（由申请方提供）：神经元迁移中断导致严重的神经和发育障碍，如认知缺陷和癫痫，主要在儿科人群中发现。神经元迁移和大脑发育的信号通路是由进化上保守的糖蛋白Reelin启动的。人类在Reelin途径中的突变产生的表型模拟了细胞骨架蛋白突变诱导的表型，这些突变破坏了微管和肌动蛋白的功能。这些儿童遗传学研究的结果强烈表明，包括Reelin通路在内的几种信号通路会聚在下游细胞骨架蛋白上，以影响适当的神经元迁移、大脑发育和认知。我们使用了系统生物学方法来确定微管稳定CLASP2作为一个关键的细胞骨架的Reelin信号调节剂。我们先前发现CLASP2在体外神经元发育过程中调节几种重要的表型，包括高尔基体形态、神经元分支、轴突特化和突触活性，这些表型也受Reelin信号转导调节。然而，关于CLASP2的作用及其与发育中大脑中的Reelin信号通路的关联知之甚少。因此，我们的目标是了解在神经元和大脑发育过程中，Reelin信号如何调节CLASP2介导的细胞骨架功能。在第一个目标中，我们将定义CLASP2与Dab1（Reelin途径中的下游节点）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，我们将定义CLASP2在大脑发育过程中的体内功能。拟议的研究旨在促进对Reelin如何通过细胞骨架重组控制神经元迁移的理解，细胞骨架重组是正常大脑发育的关键因素。

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.