Abstract 5297: Myocardin Is Required For Heart Development
Myocardin (Myocd) is a potent transcriptional coactivator that has been implicated in cardiovascular development. Myocardin is expressed as early as embryonic day (E) 7.75 in the cardiac crescent and subsequently it is expressed in embryonic heart, visceral and vascular smooth muscle cells. Myocardin-null mouse embryos survive to E10.5, precluding assessment of its function in the embryonic and late fetal heart. To address this question, genetically engineered mice were generated harboring a conditional null mutation in the Myocd gene. Myocd conditional mutants were intercrossed with Nkx2.5-Cre transgenic mice to selectively ablate the Mycod gene in cardiomyocytes. MyocdF/F/Nkx2.5-Cre+ mutant embryos survive only until E13.5 and exhibit evidence of heart failure including pericardial effusion and gross edema. Mutant hearts demonstrated markedly reduced thickness of the compact zone, decreased trabeculation, and disorganization of the interventricular septum. Cardiomyocyte proliferation quantified by BrdU incorporation and phospho-histone H3 staining was reduced in E12.5 mutant embryos. Moreover, TUNEL staining of E12.5 mutant embryos revealed massive apoptosis in cardiomyocytes. Immunostaining for myofibrillar proteins revealed striking disorganization of sarcomeric structure. Ultrastructural analysis revealed abnormal desmosome structure and disorganized intercalated discs in mutant cardiomyocytes. Gene expression analysis revealed marked down-regulation of N-Myc, Nkx2.5, ANF and MLC2v in mutant hearts. Taken together, these data provide strong evidence that in vivo myocardin is required for development of the embryonic heart and cardiomyocyte differentiation. These data suggest a model wherein myocardin is required for sarcomerogenesis and cardiomyocyte survival.