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

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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.