Although the cerebral cortex is responsible for all the intellectual life that makes us human, we know remarkably little about how this amazing structure is formed. We do know, however, that genetic conditions in which the cortex is not formed properly have devastating consequences. Neurological disorders are frequently associated with developmental brain malformations. Progress toward understanding the pathologic basis of these diseases has so far come from research on animal models of cortical malformation and from molecular genetic approaches to human neuronal migration disorders.The aim of this 3-year project is to elucidate the molecular and cellular mechanisms of one of the Planar Cell Polarity (PCP) genes,Scribble 1 (Scrib1) and Vangl2, in shaping the mammalian cortex. More specifically, the fellow applicant will analyze the role of these genes in neuronal polarity and migration. He plans to use conditional knockout mice combined with advanced cell imaging analysis and in vitro experiments that will synergize to provide a powerful approach to address this goal. We believe that the experiments from this proposal should bringnovel insight into the mechanism by which PCP genes can regulate neuronal migration and cortical development.Results from proposed experiments will bridge our knowledge from molecular mechanism of cortical neuronal migration to the formation of human brain, and will also provide important insight into the pathogenesis of human neurogenetic disorders. The candidate has a background in biomedical science, and has had intensive training in molecular approaches during Ph.D. and postdoctoral training. He now seeks further training in mouse genetics and neuroanatomy under the mentorship of Drs. Mireille Montcouquiol. With help of CIG grant, this training will greatly enhance the candidate's potential in conducting independent scientific research and reaching permanent position.