ASF/SF2-Regulated CaMKIIδ Alternative Splicing Temporally Reprograms Excitation-Contraction Coupling in Cardiac Muscle
Copyright policy )ASF/SF2-Regulated CaMKIIδ Alternative Splicing Temporally Reprograms Excitation-Contraction Coupling in Cardiac Muscle
The transition from juvenile to adult life is accompanied by programmed remodeling in many tissues and organs, which is key for organisms to adapt to the demand of the environment. Here we report a novel regulated alternative splicing program that is crucial for postnatnal heart remodeling in the mouse. We identify the essential splicing factor ASF/SF2 as a key component of the program, regulating a restricted set of tissue-specific alternative splicing events during heart remodeling. Cardiomyocytes deficient in ASF/SF2 display an unexpected hypercontraction phenotype due to a defect in postnatal splicing switch of the Ca(2+)/calmodulin-dependent kinase IIdelta (CaMKIIdelta) transcript. This failure results in mistargeting of the kinase to sarcolemmal membranes, causing severe excitation-contraction coupling defects. Our results validate ASF/SF2 as a fundamental splicing regulator in the reprogramming pathway and reveal the central contribution of ASF/SF2-regulated CaMKIIdelta alternative splicing to functional remodeling in developing heart.
- King’s University United States
- National Institute of Health Pakistan
- University of California, San Diego United States
- Columbia University United States
- University of California, San Diego United States
Male, Mice, Knockout, Serine-Arginine Splicing Factors, Biochemistry, Genetics and Molecular Biology(all), Myocytes, Smooth Muscle, 610, Gene Expression Regulation, Developmental, Nuclear Proteins, RNA-Binding Proteins, Exons, In Vitro Techniques, Transfection, Myocardial Contraction, Isoenzymes, Alternative Splicing, Mice, Phenotype, Calcium-Calmodulin-Dependent Protein Kinases, Animals, Humans, Female, Calcium-Calmodulin-Dependent Protein Kinase Type 2
Male, Mice, Knockout, Serine-Arginine Splicing Factors, Biochemistry, Genetics and Molecular Biology(all), Myocytes, Smooth Muscle, 610, Gene Expression Regulation, Developmental, Nuclear Proteins, RNA-Binding Proteins, Exons, In Vitro Techniques, Transfection, Myocardial Contraction, Isoenzymes, Alternative Splicing, Mice, Phenotype, Calcium-Calmodulin-Dependent Protein Kinases, Animals, Humans, Female, Calcium-Calmodulin-Dependent Protein Kinase Type 2
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