ASF/SF2-Regulated CaMKIIδ alternative splicing temporally reprograms excitation-contraction coupling in cardiac muscle
ASF/SF2-Regulated CaMKIIδ alternative splicing temporally reprograms excitation-contraction coupling in cardiac muscle
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DOI：
10.1016/j.cell.2004.11.036
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发表时间：
2005-01-14
期刊：
影响因子：
64.5
通讯作者：
Fu, XD
中科院分区：
文献类型：
--
作者：
Xu, XD;Yang, DM;Fu, XD
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。在这里，我们报告了一种新的调节可变剪接程序，这是至关重要的产后心脏重塑小鼠。我们确定了必要的剪接因子ASF/SF 2作为该计划的关键组成部分，在心脏重塑过程中调节一组有限的组织特异性选择性剪接事件。由于出生后Ca 2 +/钙调蛋白依赖性激酶II delta（CaMK II delta）转录物剪接开关缺陷，ASF/SF 2缺陷的心肌细胞显示出意想不到的过度收缩表型。这种失败的结果在错误的激酶肌膜，造成严重的兴奋收缩偶联缺陷。我们的研究结果验证了ASF/SF 2作为重编程途径中的基本剪接调节剂，并揭示了ASF/SF 2调节的CaMKII delta选择性剪接对发育中心脏功能重塑的重要贡献。
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 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.