ASF/SF2调控的CaMKIIdelta可变剪接在时间上对心肌中的兴奋-收缩偶联进行重新编程。

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

作者信息

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

机构信息

Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

出版信息

Cell. 2005 Jan 14;120(1):59-72. doi: 10.1016/j.cell.2004.11.036.

DOI:10.1016/j.cell.2004.11.036

PMID:15652482

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.

摘要

从幼年到成年的转变伴随着许多组织和器官的程序性重塑，这是生物体适应环境需求的关键。在此，我们报告了一种新型的受调控的可变剪接程序，该程序对小鼠出生后的心脏重塑至关重要。我们确定必需剪接因子ASF/SF2是该程序的关键组成部分，在心脏重塑过程中调节一组有限的组织特异性可变剪接事件。ASF/SF2缺陷的心肌细胞由于Ca(2+)/钙调蛋白依赖性激酶IIdelta（CaMKIIdelta）转录本的出生后剪接开关缺陷而表现出意想不到的过度收缩表型。这种失败导致激酶错误靶向肌膜，引起严重的兴奋-收缩偶联缺陷。我们的结果验证了ASF/SF2作为重编程途径中的基本剪接调节因子，并揭示了ASF/SF2调节的CaMKIIdelta可变剪接对发育中心脏功能重塑的核心贡献。