title: ASF/SF2-regulated CaMKIIdelta alternative splicing temporally reprograms excitation-contraction coupling in cardiac muscle.
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 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.
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Xu
authors.forename: Dongmei
authors.initials: D
authors.lastname: Yang
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Ding
authors.forename: Wang
authors.initials: W
authors.lastname: Wang
authors.forename: Pao-Hsien
authors.initials: PH
authors.lastname: Chu
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Dalton
authors.forename: Huan-You
authors.initials: HY
authors.lastname: Wang
authors.forename: John R
authors.initials: JR
authors.lastname: Bermingham
authors.forename: Zhen
authors.initials: Z
authors.lastname: Ye
authors.forename: Forrest
authors.initials: F
authors.lastname: Liu
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
authors.forename: James L
authors.initials: JL
authors.lastname: Manley
authors.forename: John
authors.initials: J
authors.lastname: Ross
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.forename: Rui-Ping
authors.initials: RP
authors.lastname: Xiao
authors.forename: Heping
authors.initials: H
authors.lastname: Cheng
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Fu
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D005091:Exons; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D016601:RNA-Binding Proteins; D000068103:Serine-Arginine Splicing Factors; D014162:Transfection
chemical_list: D007527:Isoenzymes; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D000068103:Serine-Arginine Splicing Factors; C517660:CAMK2D protein, human; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517673:Camk2d protein, mouse