A Point Mutation in Myh10 Causes Major Defects in Heart Development and Body Wall Closure
Background—The three isoforms of nonmuscle myosin II (NMII-A, NMII-B and NMII-C) play various roles during mouse embryonic development. Previous work, using knockout and hypomorphic mice, showed that MYH10 encoding myosin heavy chain II-B is critical for cardiac and brain development. Ablating or decreasing NMII-B by 80% results in cardiac (ventricular septal defect, double outlet of the right ventricle) and brain defects but not midline fusion defects. Neither NMII-A nor II-C appear to play roles in early myocardial development.
Methods and Results—We had previously generated point mutant knock-in mice and now report novel findings due to expressing motor deficient NMII-B at wild-type levels. Homozygous mice die at E14.5 in cardiac failure exhibiting abnormalities not seen in NMII-B null and hypomorphic mice: a failure in midline fusion resulting in a cleft palate, ectopia cordis, and a large omphalocele. Fusion of the sternum and endocardial cushions is impaired in the mutant mice associated with a failure in apoptosis of the mesenchyme cells. Failure to disassemble myocyte cell-cell adhesions during cardiac outflow tract development contributes to impaired outflow tract myocardialization and displacement of the aorta to the right ventricle.
Conclusions—Expression of motor impaired NMII-B disrupts normal ventral body wall closure, due to a dominant negative effect. This is not due to the loss of NMII-B function but rather to a gain-of-function resulting from prolonged crosslinking of NMII-B to actin-filaments thereby interfering with the dynamics of actomyosin cytoskeletal structure. Moreover impaired NMII-B motor activity inhibits outflow tract myocardialization leading to mis-localization of the aorta.
- Received August 7, 2013.
- Revision received March 19, 2014.
- Accepted April 6, 2014.