SELECTIVE REQUIREMENT OF MYOSIN LIGHT-CHAIN 2V IN EMBRYONIC HEART FUNCTION

Two major myosin light chain 2 isoforms are coexpressed in the early s tages of murine cardiogenesis, a cardiac ventricular isoform and a car diac atrial isoform, each of which is tightly regulated in a muscle ce ll-type-specific manner during embryogenesis (Chien, K. R., Zhu, H., K nowlton, K. U., Miller-Hance, W., van Bilsen, M., O'Brien, T. X., and Evans, S. M. (1993) Annu. Rev. Physiol. 55, 77-95). We have disrupted myosin light chain 2v gene in mice and monitored in vivo cardiac funct ion in living myosin light chain 2v -/- embryos, The mutant embryos di e at approximately embryonic day 12.5. In mutant ventricles, the myosi n light chain 2a protein level is increased and reaches levels compara ble to the myosin light chain 2v in the ventricles of wild type litter mates and is appropriately incorporated into the thick filaments of mu tant embryonic hearts, However despite the substitution of myosin ligh t chain 2a, ultrastructural analysis revealed defects in sarcomeric as sembly and an embryonic form of dilated cardiomyopathy characterized b y a significantly reduced left ventricular ejection fraction in mutant embryos compared with wild type littermates, We conclude that myosin light chain 2v may have a unique function in the maintenance of cardia c contractility and ventricular chamber morphogenesis during mammalian cardiogenesis and that a chamber-specific combinatorial code for sarc omeric assembly may exist that ultimately requires myosin light chain 2v in ventricular muscle cells.