SDF1/CXCR4 Signaling and Tangential Neuronal Migration in the Developing Cortex

描述（由申请人提供）：Cajal-Retzius （CR）细胞和gaba能中间神经元参与发育过程中的皮层组织和出生后的脑功能。两者都出生在遥远的发芽区，并切向迁移，以采用其皮质位置。CR细胞和许多中间神经元迁移到皮层最浅层的边缘区（MZ），靠近脑膜。中间神经元的另一个主要迁移途径是在较深的中间区（IZ）。调控这种迁移组织的分子线索开始被阐明，但有证据表明，重要的调控仍有待发现。我们发现SDF1在组织切向迁移的层流组织以及在皮质发生过程中保持CR细胞和中间神经元的MZ位置方面都起着至关重要的作用。本提案将在三个目标中研究SDF1和其他配体耦合到相同信号通路的作用。1)评估SDF1如何调节皮层中切向迁移神经元的分布。2)评估产前SDF1信号中断的产后后果。3)确定gi偶联胞内信号在切向神经元迁移中的作用。许多癫痫、智力低下和自闭症患者的临床功能障碍有证据表明，其部分原因是发育性皮层紊乱。事实上，据估计，15%的难治性癫痫患者的发病原因是发育缺陷。这一建议将阐明理解皮层发育过程中细胞迁移的分子控制的重要机制，并将建立皮层紊乱影响已知参与人类皮层畸形病理的细胞群的新动物模型。

DESCRIPTION (provided by applicant): Cajal-Retzius (CR) cells and GABAergic interneurons are involved in cortical organization during development and brain function postnatally. Both are born in remote germinative zones and migrate tangentially to adopt their cortical locations. CR cells and many interneurons migrate to cover the cortex in the most superficial layer of the cortex - the Marginal Zone (MZ), adjacent to the meninges. The other primary migratory route of interneurons is in the deeper Intermediate Zone (IZ). The molecular cues that regulate this migratory organization are beginning to be elucidated but there is evidence that important regulators remain to be found. We have found that SDF1 has crucial roles both in organizing the laminar organization of tangential migration and in retaining MZ position of CR cells and interneurons during corticogenesis. This proposal will examine the role of SDF1 and other ligands coupled to the same signaling pathway in three aims. 1) Assess how SDF1 regulates distribution of tangentially migrating neurons in the cortex. 2) Evaluate the postnatal consequences of prenatal disruption of SDF1 signaling. 3) Determine the role of Gi-coupled intracellular signaling in tangential neuronal migration. Relevance to Public Health Many patients with epilepsy, mental retardation and autism have evidence their clinical dysfunction results in part from developmental cortical disorganization. In fact, it is estimated that 15% of refractory epilepsy patients have developmental defects as the cause of their syndrome. This proposal will elucidate mechanisms important in understanding the molecular control of cell migration during cortical development and will establish novel animal models of cortical disorganization affecting groups of cells known to be involved in human cortical malformation pathology.