Cellular and Molecular Mechanisms of Early Cortical Development

描述（由申请人提供）：发育中的大脑皮层是遗传疾病和妊娠期暴露于毒素、感染和辐射的敏感靶点。尽管如此，皮质发育，特别是早期皮质发育的基本细胞和分子机制还没有很好地理解。使用一种新的3D皮质半球外植体的方法和报告小鼠，我们将检查启动皮质板形成的细胞行为，并确定如何分泌的配体，Reelin协调这些行为。我们将重点关注的作用，依赖于Reelin的局部粘附适配蛋白桩蛋白，我们发现动态表达在早期皮质发育和异常表达在reeler小鼠皮质缺乏Reelin的调制。我们正在使用药理学和基于RNAi的方法来靶向Reelin信号通路中的下游信号传导元件，以确定Reelin和Paxillin在触发和/或维持这种形态分化和运动性中的作用。这些研究将有助于解决Reelin功能的竞争模型，同时为大脑皮层细胞层的形成提供进一步的分子和细胞见解。深入了解Reelin在皮质发育中的作用将为整个中枢神经系统神经元的发育和组织提供一般性的见解。在成人中，Reelin在癫痫灶中上调，并对神经损伤作出反应。因此，Reelin可能在愈合和功能恢复中发挥额外的重要作用。 公共卫生相关性：脑畸形越来越被认为是某些形式的癫痫、智力迟钝、自闭症、诵读困难和阅读障碍的根本原因。该提案研究了在大脑发育的早期阶段发生的分子和细胞事件，但对后期的大脑功能和认知产生重大影响。这项工作将提供一个框架，了解大脑皮质畸形的病因。

DESCRIPTION (provided by applicant): The developing cerebral cortex is a sensitive target for genetic diseases and for gestational exposure to toxins, infection and radiation. Despite this, the basic cellular and molecular mechanisms of cortical development, particularly early cortical development are not well understood. Using a novel 3D cortical hemisphere explant approach and reporter mice, we will examine the cellular behaviors that initiate cortical plate formation and determine how the secreted ligand, Reelin coordinates these behaviors. We will focus on the role of Reelin-dependent modulation of the focal adhesion adaptor protein Paxillin that we find dynamically expressed during early cortical development and aberrantly expressed in reeler mice cortices that lack Reelin. We are using pharmacological and RNAi-based approaches to target downstream signaling elements in the Reelin signaling pathway to determine Reelin's and Paxillin's role(s) in triggering and/or sustaining this morphological differentiation and motility. These studies will help resolve competing models of Reelin function, while providing further molecular and cellular insights into the formation of a cellular layer of the cerebral cortex. Insight into Reelin's role in cortical development will provide a general insight into the development and organization of neurons throughout the central nervous system. In adults, Reelin is up regulated in epileptic foci, and in response to nerve injury. Reelin may therefore have additional important roles in healing and functional recovery. PUBLIC HEALTH RELEVANCE: Brain malformations are increasingly appreciated as an underlying cause of certain forms of epilepsy, mental retardation, autism, dyslexia and reading disorders. This proposal examines molecular and cellular events that occur at an early stage of brain development, but that have a major impact on later brain function and cognition. The work will provide a framework for understanding the etiology of cerebral cortical malformations.