MOLECULAR MECHANISMS OF NEURONAL MIGRATION

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The research described in this proposal is designed to understand the molecular mechanism on embryonic cortical neuronal migration through a series of functional studies on LIS-1, the gene responsible for human Miller-Dieker lissencephaly. Mutations in LIS-1 cause arrest in neuronal migration during early embryogenesis, and result in brain malformation and severe neurological disorders in affected individuals. Several lines of evidence have suggested that LIS-1 may function through associating with yet unidentified molecule by protein-protein interaction. Thus, the proposed functional studies on the LIS-1 gene product are first aimed at identifying LIS-1 binding proteins by two- hybrid screens, as well as by direct biochemical co-purification and filter overlay experiments. These experiments are expected to provide critical information on the molecular pathways that guide neuronal migration. The proposal is also designed to study the cell biological features of LIS-1 by analyzing the expression, subcellular distribution and posttranslational modification of the protein and its potential relation with cytoskeleton structures. Finally, cell genetic experiments are also proposed for observing the phenotype of LIS-1 overexpression, antisense inhibition and dominant negative effect in controlling neurogenesis in a cell line which only expresses LIS-1 when undergoing neuronal differentiation. Upon accomplishing these specific goals, the research proposed will allow better understandings on how human brain develops, and will further provide insight into the pathogenesis of diseases caused by brain malformation.