A post-transcriptional compensatory pathway in heterozygous ventricular myosin light chain 2-deficient mice results in lack of gene dosage effect during normal cardiac growth or hypertrophy.
Our previous study of homozygous mutants of the ventricular specific isoform of myosin light chain 2 (mlc-2v) demonstrated that mlc-2v plays an essential role in murine heart development (Chen, J., Kubalak, S. W., Minamisawa, S., Price, R. L., Becker, K. D., Hickey, R., Ross, J., Jr., and Chien, K. R. (1998) J. Biol. Chem. 273, 1252-1256). As gene dosage of some myofibrillar proteins can affect muscle function, we have analyzed heterozygous mutants in depth. Ventricles of heterozygous mutants displayed a 50% reduction in mlc-2v mRNA, yet expressed normal levels of protein both under basal conditions and following induction of cardiac hypertrophy by aortic constriction. Heterozygous mutants exhibited cardiac function comparable to that of wild-type littermate controls both prior to and following aortic constriction. There were no significant differences in contractility and responses to calcium between wild-type and heterozygous unloaded cardiomyocytes. We conclude that heterozygous mutants show neither a molecular nor a physiological cardiac phenotype either at base line or following hypertrophic stimuli. These results suggest that post-transcriptional compensatory mechanisms play a major role in maintaining the level of MLC-2v protein in murine hearts. In addition, as our mlc-2v knockout mutants were created by a knock-in of Cre recombinase into the endogenous mlc-2v locus, this study demonstrates that heterozygous mlc-2v cre knock-in mice are appropriate for ventricular specific gene targeting.
Minamisawa
S
S
Department of Medicine and the Center for Molecular Genetics, University of California at San Diego, School of Medicine, La Jolla, California 92093-0613, USA.
Gu
Y
Y
Ross
J
J
Chien
K R
KR
Chen
J
J
D000818:Animals; D015415:Biomarkers; D015153:Blotting, Western; D024722:Cardiac Myosins; D006332:Cardiomegaly / Q000473:pathology*; D004452:Echocardiography; D004591:Electrophoresis, Polyacrylamide Gel; D018628:Gene Dosage; D006321:Heart / Q000254:growth & development*; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction; D018994:Myosin Light Chains / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D011499:Protein Processing, Post-Translational
D015415:Biomarkers; D018994:Myosin Light Chains; C107184:myosin light chain 2; D024722:Cardiac Myosins