During development of the central nervous system, neurons born in proliferative zones migrate long distances to reach their final location. This process is essential for normal development and function of the nervous system. Disorders of neuronal migration play a causal role in abnormal development and dysfunction of the brain such as double cortex syndrome and epilepsy. Cerebral cortical neurons generated in the ventricular zone and subventricular zone (SVZ) migrate outward to the cortical plate along glia fibers. Olfactory interneuron precursors generated in the SVZ in the anterior forebrain (SVZa) migrate to the olfactory bulb in """"""""chains,"""""""" a process requiring the polysialic acid moiety of neural cell adhesion molecule (NCAM). The long-term goal is to elucidate the molecular mechanisms that regulate neuronal migration. The working hypothesis is that the migration of olfactory interneuron precursors and the cerebral cortical neurons is guided, in part, by an unidentified chemorepulsive factor. To test this hypothesis, the following specific aims are proposed.
Specific Aim 1 : Molecular cloning of the septum derived chemorepulsive factor by cloning the candidate molecule, gp-190.
Specific Aim 2 : Characterization and functional analysis of gp-190: Determine the role of gp-190 in the guidance of olfactory interneuron precursors and of cerebral cortical neurons. These studies would identify a long-range guidance molecule for migrating neurons and should provide further insight into molecular mechanisms of neuronal migration and contribute to the understanding of root causes of brain dysfunctions such as X-linked Kallman syndrome, mental retardation, and epilepsy.
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