Abstract 1057: MRTF-A and MRTF-B Mediate Redundant Functions Required for Cardiac Development
Myocardin and the myocardin-related transcription factors (MRTFs) -A and -B are transcriptional coactivators that have been implicated in cytoskeletal signaling and vascular development. Myocardin null mice die at embryonic day (E)10.5 and demonstrate no evidence of vascular smooth muscle cell (SMC) differentiation. MRTF-B null mice generally die at birth from a spectrum of cardiac outflow tract defects related to failure of the cardiac neural crest to differentiate into SMCs. To determine the function of MRTF-A in vivo, the MRTF-A gene was targeted in embryonic stem cells and MRTF-A null (−/−) mice were generated and characterized. Surprisingly, MRTF-A null mice were phenotypically indistinguishable from their control littermates without obvious cardiovascular defects. Therefore, MRTF-A−/− and MRTF-B+/− mice were intercrossed to determine whether these related transcription factors mediate redundant functions in the cardiovascular system. Compound heterozygotes (MRTF-A+/−/MRTF-B+/−) were born in the expected Mendelian ratio, but they exhibited a persistent ventricular septal defect (VSD). By contrast, 50% of MRTF-A−/−/MRTF-B+/− mice died between E14.5 and birth from heart failure. Histological examination of their hearts revealed near total obliteration of the ventricular cavities from proliferating cardiomyocytes. Finally, compound homozygotes (MRTF-A−/−/MRTF-B−/−) survived only to E9.5 exhibiting a severe block in looping morphogenesis. Taken together, these data reveal that MRTF-A and -B mediate partially overlapping, and redundant, functions required at multiple distinct stages of embryonic heart development. These data serve to identify MRTF-A and -B and genes regulated by these two related transcriptional co-activators in the pathogenesis of common forms of congenital heart disease.