Journal
CIRCULATION RESEARCH
Volume 99, Issue 3, Pages 323-331Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000234807.16034.fe
Keywords
cardiac myosin light chain-2; myofibrillogenesis; zebrafish heart
Funding
- NHLBI NIH HHS [5R01HL49579, 1R01HL63206] Funding Source: Medline
- NIA NIH HHS [K01 AG023562] Funding Source: Medline
- NIDDK NIH HHS [5R01DK55383] Funding Source: Medline
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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 (tel(m225)), 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.
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