Published online before print July 31, 2003, doi: 10.1161/01.RES.0000089256.00309.CB
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© 2003 American Heart Association, Inc.
Cellular Biology |
Ablation and Mutation of Nonmuscle Myosin Heavy Chain II-B Results in a Defect in Cardiac Myocyte Cytokinesis
From the Laboratory of Molecular Cardiology (K.T., H.K., X.M., R.S.A.) and Pathology Core Facility (Z.-X.Y.), National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md; Department of Molecular Physiology (H.K.), Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan.
Correspondence to Dr Robert S. Adelstein, National Institutes of Health, Bldg 10, Room 8N202, 10 Center Dr MSC 1762, Bethesda, MD 20892-1762. E-mail AdelsteR{at}nhlbi.nih.gov
We have identified a novel form of cardiac myocyte enlargement in nonmuscle myosin heavy chain II-B (NMHC II-B) ablated mice, based on a partial failure in cytokinesis. In contrast to most cells, cardiac myocytes lack NMHC II-A, and ablation of NMHC II-B results in a heart with 70% fewer myocytes at embryonic day 14.5 (E14.5) than control mice (B+/B- and B+/B+). In addition, B-/B- cardiac myocytes show a marked increase in binucleation at E12.5, reflecting the occurrence of karyokinesis in the absence of cytokinesis. An increase in binucleation and cell size is also found in hypomorphic, homozygous mice harboring a single amino acid mutation (R709C) in the gene encoding NMHC II-B. The nonmyocytes in B-/B- hearts and homozygous mutant hearts, all of which contain NMHC II-A, do not show either of these abnormalities. B-/B- cardiac myocytes at E14.5 show a decreased bromodeoxyuridine (BrdU) labeling index compared with controls, consistent with the decrease in myocyte proliferation. This decreased BrdU labeling is not seen in nonmyocyte cells in the heart. In addition to these changes, both B-/B- mice as well as homozygous mutated mice show an increase in cyclin D2 and D3 reflecting an abnormality in earlier steps in the cell cycle. Whereas cardiac myocytes completely ablated for NMHC II-B show enlargement and binucleation, mice expressing as little as 6% of the normal amount of wild-type NMHC II-B in the heart do not show these abnormalities.
Key Words: cell cycle • heart development • immunohistochemistry • myocyte enlargement • bromodeoxyuridine labeling index
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