ASF/SF2-regulated CaMKIIδ alternative splicing temporally reprograms excitation-contraction coupling in cardiac muscle

Xiangdong Xu, Dongmei Yang, Jian Hua Ding, Wang Wang, Pao Hsien Chu, Nancy D. Dalton, Huan You Wang, John R. Bermingham, Zhen Ye, Forrest Liu, Michael G. Rosenfeld, James L. Manley, John Ross, Ju Chen, Rui Ping Xiao, Heping Cheng, Xiang Dong Fu

Research output: Contribution to journalArticlepeer-review

258 Scopus citations

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.

Original languageEnglish
Pages (from-to)59-72
Number of pages14
JournalCell
Volume120
Issue number1
DOIs
StatePublished - Jan 14 2005

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