Characterization of Gli3 function during development of the corpus callosum: a model for the pathogenesis of ACS and GCPS Syndrome

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Mental Retardation (MR) is a relatively common form of cognitive impairment affecting 1%- 3% of the population. Understanding the biology of MR is complicated by the extraordinary heterogeneity of MR disorders. Acrocallosal syndrome (ACS) represenst a specific form of MR which is characterized by the absence of the corpus callosum, the mafor fiber tract connecting the left and right cerebral hemisphere. Also, a subset of Greig cephalopolydactyly syndrome (GCPS) patients are mentally retarded and both syndromes can be caused by mutations in the zinc finger transcription factor gene GLI3.My lab has a major interest in characterizing the role of Gli3 during development of the cerebral cortex. In this proposal we want to use Gli3 mutant mice as a model to elucidate the mechanisms leading to the absence of the corpus callosum in these animals and by interference in ACS/GCPS patients. We will use Dil tracing techniques to examine axonal projections of cortical neurons and in situ hybrdization and immunohistochemical analysis to define the molecular and cellular basis for the agenesis of the corpus callosum. From this analysis we expect further clues to our understanding of the causes underlying MR which is ultimatively required for defining potential treatments of MR patients.