Cell
Volume 120, Issue 1, 14 January 2005, Pages 59-72
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Article
ASF/SF2-Regulated CaMKIIδ Alternative Splicing Temporally Reprograms Excitation-Contraction Coupling in Cardiac Muscle

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Abstract

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 Ca2+/calmodulin-dependent kinase IIδ (CaMKIIδ) 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 CaMKIIδ alternative splicing to functional remodeling in developing heart.

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6

These authors contributed equally to this work.

7

Present address: The First Cardiovascular Department, Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taipei, Taiwan.

8

Present address: Department of Pathology and Laboratory Medicine, The Hospital of University of Pennsylvania, Philadelphia, Pennsylvania 19104.

9

Present address: McLaughlin Research Institute, 1520 23rd Street South, Great Falls, Montana 59405.