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，皮层发育的基本细胞和分子机制，特别是早期皮层发育的机制还没有得到很好的理解。使用一种新的3D皮质半球外植体方法和报告小鼠，我们将研究启动皮质板形成的细胞行为，并确定分泌的配体Reelin如何协调这些行为。我们将重点关注依赖于Reelin的局点粘附接头蛋白Paxillin的调节作用，我们发现Paxillin在早期皮质发育过程中动态表达，在缺乏Reelin的reeler小鼠皮质中异常表达。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元件，以确定Reelin和Paxillin在触发和/或维持这种形态分化和运动中的作用。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个总体的见解。在成人中，Reelin在癫痫病灶和神经损伤中被上调。因此，芦苇可能在愈合和功能恢复中具有额外的重要作用。

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.