Transcriptional control of cardiovascular development

Members of the myocyte enhancer faclor-2 (MEF2) familv of MA!)S-bo\ transcription factors bind A/T-rich ON A sequence associated with muscle-specific genes and are expressed throughout the cardiac, skeletal, and smooth muscle cell lineages during embryogenesis of vertebrates and fruit flies- Previous studies have demonstrated that the single MEF2 gene in Drosophila is required for differentiation of all muscle cell types in the embryo. Vertebrates contain four MKF2 genes, referred to as \)l-'.F2.4 H ( V We have generated mice lacking each of these genes MEF2C mutant mice die at emlmonic day 10 and show severe defects in development of the cardiovascular system. In M HOC mutant embryos, the heart fails to undergo looping morphogenesis, the right ventricle does not form, and a subset of cardiac muscle genes is not expressed Smooth muscle cells also do not differentiate and the vascular system does not form in the absence oi MKF2C. These results demonstrate that MEF2C is an essential component of the regulatorv programs required for morphogenesis and myogenesis in the developing cardiovascular system. The unique and potemially overlapping functions of the other MEF2 genes are being determined by analysis of mice lacking each gene and b> intercrosses of different MKF2 mutant mouse lines. Members of the MF.F2 family have been shown to regulate skeletal muscle development by interacting with myogemu bHLH proteins to establish a combinatorial code for skeletal muscle gene activation. Potential partners for MF.F2 in the cardiovascular system u til be discussed.