Cardiac myosin light chain-2: a novel essential component of thick-myofilament assembly and contractility of the heart.
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.
Rottbauer
Wolfgang
W
Department of Medicine III, University of Heidelberg, Germany. wolfgang.rottbauer@med.uni-heidelberg.de
Wessels
Georgia
G
Dahme
Tillman
T
Just
Steffen
S
Trano
Nicole
N
Hassel
David
D
Burns
Charles Geoffrey
CG
Katus
Hugo A
HA
Fishman
Mark C
MC
D000818:Animals; D024722:Cardiac Myosins / Q000378:metabolism / Q000502:physiology*; D004625:Embryo, Nonmammalian; D006321:Heart / Q000196:embryology / Q000254:growth & development* / Q000502:physiology*; D006325:Heart Atria / Q000166:cytology; D006352:Heart Ventricles / Q000166:cytology; D024510:Muscle Development; D009154:Mutation; D009200:Myocardial Contraction; D018994:Myosin Light Chains / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D015027:Zebrafish
D018994:Myosin Light Chains; C107184:myosin light chain 2; D024722:Cardiac Myosins