The MEF2C transcription factor is essential for cardiac morphogenesis and myogenesis in mice. In mice with a null mutation of MEF2C, the heart tube failed to undergo looping morphogenesis, the right ventricle did not form, and a subset of cardiac muscle genes was not expressed. The absence of the right ventricular region correlated with down-regulation of the dHAND gene, which is required for cardiac morphogenesis. These findings indicate that MEF2C is a critical regulator of cardiac development. MEF2C is expressed in cardiogenic precursor cells and differentiated cardiomyocytes during embryogenesis. It is also expressed in skeletal and smooth muscle cell lineages. MEF2C is part of the MEF2 family of transcription factors, which bind a conserved A-T-rich DNA sequence associated with most cardiac muscle structural genes. The MEF2 family includes four genes: MEF2A, -B, -C, and -D. These genes share homology in an N-terminal MADS-box and an adjacent motif known as the MEF2 domain. In the mouse, MEF2B and MEF2C are co-expressed in the precardiogenic mesoderm beginning at embryonic day 7.75, and MEF2A and MEF2D are expressed about 12 hours later. MEF2 gene expression is detected in skeletal muscle precursors in the somites and in smooth muscle cells beginning at about E9.0. Loss-of-function mutations in a single MEF2 gene in Drosophila, D-mef2, prevent differentiation of cardiac, skeletal, and visceral muscle cells. However, the functions of the vertebrate MEF2 genes in the embryo have not been determined. To investigate MEF2C function during mouse embryogenesis, the gene was inactivated with a targeting vector that deleted the second protein-coding exon. The MEF2C null mutation resulted in embryonic lethality, with no viable mutants observed by E10.5. The most obvious morphologic defects in mutant embryos were within the heart. The heart tube did not undergo rightward looping, and there was no morphologic evidence of the future right ventricle. The atrioventricular (AV) demarcation was apparent in the mutant, but the AV canal did not elongate. The sinus venosus, which normally forms from the posterior portion of the atrial chamber, did not form in the mutant. The cardiogenic defects seen in MEF2C mutant embryos are distinct from those seen in other mouse mutants. The phenotype of MEF2C mutant embryos demonstrates that MEF2C is required for looping of the cardiac tube, development of the right ventricle, and expression of a subset of cardiac muscle genes. The absence of MEF2C led to the down-regulation of several cardiac muscle genes, including atrial natriuretic factorThe MEF2C transcription factor is essential for cardiac morphogenesis and myogenesis in mice. In mice with a null mutation of MEF2C, the heart tube failed to undergo looping morphogenesis, the right ventricle did not form, and a subset of cardiac muscle genes was not expressed. The absence of the right ventricular region correlated with down-regulation of the dHAND gene, which is required for cardiac morphogenesis. These findings indicate that MEF2C is a critical regulator of cardiac development. MEF2C is expressed in cardiogenic precursor cells and differentiated cardiomyocytes during embryogenesis. It is also expressed in skeletal and smooth muscle cell lineages. MEF2C is part of the MEF2 family of transcription factors, which bind a conserved A-T-rich DNA sequence associated with most cardiac muscle structural genes. The MEF2 family includes four genes: MEF2A, -B, -C, and -D. These genes share homology in an N-terminal MADS-box and an adjacent motif known as the MEF2 domain. In the mouse, MEF2B and MEF2C are co-expressed in the precardiogenic mesoderm beginning at embryonic day 7.75, and MEF2A and MEF2D are expressed about 12 hours later. MEF2 gene expression is detected in skeletal muscle precursors in the somites and in smooth muscle cells beginning at about E9.0. Loss-of-function mutations in a single MEF2 gene in Drosophila, D-mef2, prevent differentiation of cardiac, skeletal, and visceral muscle cells. However, the functions of the vertebrate MEF2 genes in the embryo have not been determined. To investigate MEF2C function during mouse embryogenesis, the gene was inactivated with a targeting vector that deleted the second protein-coding exon. The MEF2C null mutation resulted in embryonic lethality, with no viable mutants observed by E10.5. The most obvious morphologic defects in mutant embryos were within the heart. The heart tube did not undergo rightward looping, and there was no morphologic evidence of the future right ventricle. The atrioventricular (AV) demarcation was apparent in the mutant, but the AV canal did not elongate. The sinus venosus, which normally forms from the posterior portion of the atrial chamber, did not form in the mutant. The cardiogenic defects seen in MEF2C mutant embryos are distinct from those seen in other mouse mutants. The phenotype of MEF2C mutant embryos demonstrates that MEF2C is required for looping of the cardiac tube, development of the right ventricle, and expression of a subset of cardiac muscle genes. The absence of MEF2C led to the down-regulation of several cardiac muscle genes, including atrial natriuretic factor