Published online before print June 29, 2006, doi: 10.1161/01.RES.0000234807.16034.fe
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Submitted on March 2, 2006
Revised on May 31, 2006
Accepted on June 15, 2006
Cardiac Myosin Light Chain-2. A Novel Essential Component of Thick-Myofilament Assembly and Contractility of the Heart
Wolfgang Rottbauer *;
From the Department of Medicine III (W.R., G.W., T.D., S.J., N.T., D.H., H.A.K.), University of Heidelberg, Germany; Cardiovascular Research Center (W.R., C.G.B., M.C.F.), Massachusetts General Hospital, and Department of Medicine, Harvard Medical School, Boston, Mass; and Novartis Institutes for BioMedical Research (M.C.F.), Cambridge, Mass.
* To whom correspondence should be addressed. E-mail: wolfgang.rottbauer{at}med.uni-heidelberg.de.
Although it is well known that mutations in the cardiac regulatory myosin light chain-2 (mlc-2) gene cause hypertrophic cardiomyopathy, the precise in vivo structural and functional roles of MLC-2 in the heart are only poorly understood. We have isolated a mutation in zebrafish, tell tale heart (telm225), which selectively perturbs contractility of the embryonic heart. By positional cloning, we identified tel to encode the zebrafish mlc-2 gene. In contrast to mammals, zebrafish have only 1 cardiac-specific mlc-2 gene, which we find to be expressed in atrial and ventricular cardiomyocytes during early embryonic development, but also in the adult heart. Accordingly, loss of zMLC-2 function cannot be compensated for by upregulation of another mlc-2 gene. Surprisingly, ultrastructural analysis of tel cardiomyocytes reveals complete absence of organized thick myofilaments. Thus, our findings provide the first in vivo evidence that cardiac MLC-2 is required for thick-filament stabilization and contractility in the vertebrate heart.
Key words: cardiac myosin light chain-2 • myofibrillogenesis • zebrafish heart
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