Nonmuscle myosin II-B is required for normal development of the mouse heart

Nonmuscle myosin II-B is required for normal development of the mouse heart

^*Laboratory of Molecular Cardiology and ^‡Pathology Section, National Heart, Lung, and Blood Institute; and ^†Developmental Endocrinology Branch and ^§Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892

Edited by Thomas D. Pollard, The Salk Institute, La Jolla, CA, and approved September 10, 1997 (received for review June 12, 1997)

Abstract

We used targeted gene disruption in mice to ablate nonmuscle myosin heavy chain B (NMHC-B), one of the two isoforms of nonmuscle myosin II present in all vertebrate cells. Approximately 65% of the NMHC-B ^−/− embryos died prior to birth, and those that were born suffered from congestive heart failure and died during the first day. No abnormalities were detected in NMHC-B ^+/− mice. The absence of NMHC-B resulted in a significant increase in the transverse diameters of the cardiac myocytes from 7.8 ± 1.8 μm (right ventricle) and 7.8 ± 1.3 μm (left ventricle) in NMHC-B ^+/+ and B ^+/− mice to 14.7 ± 1.1 μm and 13.8 ± 2.3 μm, respectively, in NMHC-B ^−/− mice (in both cases, P < 0.001). The increase in size of the cardiac myocytes was seen as early as embryonic day 12.5 (4.5 ± 0.2 μm for NMHC-B ^+/+ and B ^+/− vs. 7.2 ± 0.6 μm for NMHC-B ^−/− mice (P < 0.01)). Six of seven NMHC-B ^−/− newborn mice analyzed by serial sectioning also showed structural cardiac defects, including a ventricular septal defect, an aortic root that either straddled the defect or originated from the right ventricle, and muscular obstruction to right ventricular outflow. Some of the hearts of NMHC-B ^−/− mice showed evidence for up-regulation of NMHC-A protein. These studies suggest that nonmuscle myosin II-B is required for normal cardiac myocyte development and that its absence results in structural defects resembling, in part, two common human congenital heart diseases, tetralogy of Fallot and double outlet right ventricle.

Footnotes

↵ ¶ To whom reprint requests should be addressed at: National Institutes of Health, Building 10, Room 8N202, 10 Center Drive MSC 1762, Bethesda, MD 20892-1762. e-mail: RA19t{at}nih.gov.
This paper was submitted directly (Track II) to the Proceedings Office.
Abbreviations: En, embryonic day n; ES, embryonic stem; NMHC, nonmuscle myosin heavy chain; VSD, ventricular septal defect; Neo^r, resistant to neomycin.