Mutations in the X-linked locus, XLis, produce isolated lissencephaly sequence (ILS) in hemizygous males and subcortical band heterotopia (SBH, or double cortex, DC). XLis encodes Dbcn, a novel cytosolic protein with a region of homology to a novel calcium calmodulin dependent kinase, a putative cAbl tyrosine phosphorylation site, and a Ser/Pro rich domain possibly important in protein/protein interactions. This project proposes to produce several mouse models to investigate the role of Dbcn in neuronal migration. Initially, loss of function mutations in XLis will be produced by homologous recombination. Neuronal migration will be examined in cortical slice cultures prepared from XLis null, XLis and Lis1 heterozygous embryos. Embryos with mutations in both XLis and Lis1 or XLis and mDab1 will be examined to determine possible interactions between the products of these genes. Lastly, transgenic mice over-expressing Dbcn will be produced to determine if defective regulation of this protein results in aberrant neuronal migration.
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