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萌发区，并切向迁移，以适应他们的皮层位置。CR细胞和许多中间神经元迁移以覆盖皮质最表层的皮质-边缘区（MZ），邻近脑膜。中间神经元的另一个主要迁移路线是在更深的中间区（IZ）。调节这种迁移组织的分子线索开始被阐明，但有证据表明，重要的监管机构仍有待发现。我们已经发现，SDF 1具有至关重要的作用，在组织的层流组织切线迁移和保留MZ的CR细胞和interneurons在corticogenesis的位置。该提案将研究SDF 1和其他配体在三个目标中与相同信号通路偶联的作用。1)评估SDF 1如何调节皮层中切向迁移神经元的分布。2)评估产前SDF 1信号传导中断的产后后果。3)确定Gi偶联细胞内信号传导在切向神经元迁移中的作用。与公共卫生的相关性许多癫痫、精神发育迟滞和自闭症患者有证据表明，他们的临床功能障碍部分是由于发育性皮质紊乱。事实上，据估计，15%的难治性癫痫患者有发育缺陷作为其综合征的原因。这项建议将阐明机制，重要的是在了解皮质发育过程中的细胞迁移的分子控制，并将建立新的动物模型皮质紊乱影响组细胞已知参与人类皮质畸形病理。

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.