MICE LACKING THE SKI PROTOONCOGENE HAVE DEFECTS IN NEURULATION, CRANIOFACIAL PATTERNING, AND SKELETAL-MUSCLE DEVELOPMENT

The c-ski proto-oncogene has been implicated in the control of cell gr owth and skeletal muscle differentiation. To determine its normal func tions in vivo, we have disrupted the mouse c-ski gene. Our results sho w a novel role for ski in the morphogenesis of craniofacial structures and the central nervous system, and confirm its proposed function as a player in skeletal muscle development. Homozygous mutant mice show p erinatal lethality resulting from exencephaly, a defect caused by fail ed closure of the cranial neural tube during neurulation. The timing o f the neural tube defect in ski -/- embryos coincides with excessive a poptosis in the cranial neuroepithelium, as well as in the cranial mes enchyme. Homozygous ski mutants also exhibit a dramatic reduction in s keletal muscle mass, consistent with a defect in expansion of a myogen ic precursor population. Nestin is an intermediate filament expressed in highly proliferative neuroepithelial stem cells and in myogenic pre cursors. Interestingly, we find decreased nestin expression in both th e cranial neural tube and the somites of ski -/- embryos, compared wit h their normal littermates, but no reduction of nestin in the caudal n eural tube. These results are consistent with a model in which ski act ivities are required for the successful expansion of a subset of precu rsors in the neuroepithelial or skeletal muscle lineages.