NONMUSCLE MYOSIN II-B IS REQUIRED FOR NORMAL DEVELOPMENT OF THE MOUSEHEART

We used targeted gene disruption in mice to ablate nonmuscle myosin he avy chain B (NMHC-B), one of the two isoforms of nonmuscle myosin II p resent in all vertebrate cells, Approximately 65% of the NMHC-B-/- emb ryos died prior to birth, and those that were born suffered from conge stive heart failure and died during the first day, No abnormalities we re detected in NMHC-B+/- mice. The absence of NMHC-B resulted in a sig nificant increase in the transverse diameters of the cardiac myocytes from 7.8 +/- 1.8 mu m (right ventricle) and 7.8 +/- 1.3 mu m (left ven tricle) in NMHC-B+/+ and B+/- mice to 14.7 +/- 1.1 mu m and 13.8 +/- 2 .3 mu m, respectively, in NMHC-B-/- mice (in both cases, P < 0.001), T he increase in size of the cardiac myocytes was seen as early as embry onic day 12.5 (4.5 +/- 0.2 mu m for NMHC-B+/+ and B+/- vs. 7.2 +/- 0.6 mu m for NMHC-B-/- mice (P < 0.01)), Six of seven NMHC-B-/- newborn m ice analyzed by serial sectioning also showed structural cardiac defec ts, including a ventricular septal defect, an aortic root that either straddled the defect or originated from the right ventricle, and muscu lar obstruction to right ventricular outflow, Some of the hearts of NM HC-B-/- mice showed evidence for up-regulation of NMHC-A protein, Thes e studies suggest that nonmuscle myosin II-B is required for normal ca rdiac myocyte development and that its absence results in structural d efects resembling, in part, two common human congenital heart diseases , tetralogy of Fallot and double outlet right ventricle.