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

描述(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质组织和出生后的大脑功能。两者都出生在偏远的发育区，并以切线方式迁徙以适应它们的皮质位置。CR细胞和许多中间神经元迁移到皮质最浅的一层，即与脑膜相邻的边缘地带(MZ)，覆盖皮质。中间神经元的另一条主要迁移路线是在更深的中间带(IZ)。调控这一迁徙组织的分子线索开始被阐明，但有证据表明，重要的调控因素仍有待发现。我们发现SDF1在组织切向迁移的层状组织和在皮质发生过程中维持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。这项建议将研究SDF1和其他连接到同一信号通路的配体在三个目标中的作用。1)评估SDF1如何调节大脑皮层切向迁移神经元的分布。2)评估SDF1信号在出生前中断的出生后后果。3)确定GI偶联的细胞内信号在切向神经元迁移中的作用。与公共卫生相关许多癫痫、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组织紊乱造成的。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。这项建议将阐明在理解皮质发育过程中细胞迁移的分子控制方面的重要机制，并将建立影响已知的与人类皮质畸形病理有关的细胞组的皮质紊乱的新动物模型。

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.