TARGETED DISRUPTION OF EMXL GENE ACTIVITY

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The experiments described in this proposal are designed to examine the role of the mouse Emx1 gene during brain development. Emx1 is expressed in a limited region of the forebrain during early embryonic development. Emx1 contains a homeobox, giving its gene product the ability to bind DNA and potentially to regulate transcription. Pattern formation in the vertebrate central nervous system relies on the regional expression and activity of genes which regulate transcription; these experiments will test whether Emx1 may be a gene active in pattern formation. Emx1 function will be studied using gene targeting to disrupt the activity of the gene in vivo. Animals will then be analyzed for anatomical and behavioral changes stemming from engineered mutation. If Emx1 acts during pattern formation, it is likely to specify the regional identity of part of the brain in which it is expresses; anatomical rearrangements of this area will define whether the forebrain requires Emx1 activity for its development. Mutations in a closely related human gene, the EMX2 gene, are linked to schizencephaly, suggesting a requirement for the EMX2 protein for proper cell migration during central nervous system development. It is likely that the Emx1 gene is also critical for anterior brain development: the proposed experiments will test this hypothesis and define how and where Emx1 acts during development. Comparison of the defects identified in mutant mice with clinical information about brain defects in humans may then uncover congenital brain disorders which are linked to mutations in the human EMX1 gene.