A point mutation in Myh10 causes major defects in heart development and body wall closure.
BACKGROUND
The 3 isoforms of nonmuscle myosin (NM) 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 seems to play roles in early myocardial development.


RESULTS
We had previously generated point mutant knock-in mice and now report novel findings as a result of expressing motor-deficient NMII-B at wild-type levels. Homozygous mice die at embryonic day 14.5 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 mesenchymal 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 because of a dominant-negative effect. This is not because of the loss of NMII-B function but rather a gain-of-function resulting from prolonged cross-linking of NMII-B to actin filaments, thereby interfering with the dynamics of actomyosin cytoskeletal structure. Furthermore, impaired NMII-B motor activity inhibits outflow tract myocardialization, leading to mislocalization of the aorta.
From the Laboratory of Molecular Cardiology, Genetics & Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD. MaX@nhlbi.nih.gov.
Xuefei
X
Ma
From the Laboratory of Molecular Cardiology, Genetics & Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
Robert S
RS
Adelstein
D000818:Animals; D006321:Heart / Q000196:embryology* / Q000503:physiopathology; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006352:Heart Ventricles / Q000002:abnormalities* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D018345:Mice, Knockout; D018995:Myosin Heavy Chains / Q000235:genetics* / Q000378:metabolism; D024501:Nonmuscle Myosin Type IIB / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation
D024501:Nonmuscle Myosin Type IIB; C103815:nonmuscle myosin type IIB heavy chain; D018995:Myosin Heavy Chains
apoptosis; cell adhesion; double outlet right ventricle; ectopia cordis; hernia, diaphragmatic; nonmuscle myosin type IIA