Zhang Xiaoli, Wang Ze, Xu Qing, Chen Yuhan, Liu Wen, Zhong Tong, Li Hongchang, Quan Chengshi, Zhang Lingqiang, Cui Chun-Ping
The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, Jilin 130021, China.
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, 27 Taiping Road, Beijing 100850, China.
iScience. 2021 Sep 10;24(10):103097. doi: 10.1016/j.isci.2021.103097. eCollection 2021 Oct 22.
The serine/arginine-rich (SR) family of splicing factors plays important roles in mRNA splicing activation, repression, export, stabilization, and translation. SR-splicing factor 5 (SRSF5) is a glucose-inducible protein that promotes tumor cell growth. However, the functional role of SRSF5 in tissue development and disease remains unknown. Here, knockout ( ) mice were generated using CRISPR-Cas9. Mutant mice were perinatally lethal and exhibited cardiac dysfunction with noncompaction of the ventricular myocardium. The left ventricular internal diameter and volume were increased in mice during systole. Null mice had abnormal electrocardiogram patterns, indicative of a light atrioventricular block. Mechanistically, Srsf5 promoted the alternative splicing of Myom1 (myomesin-1), a protein that crosslinks myosin filaments to the sarcomeric M-line. The switch between embryonic and adult isoforms of Myom1 could not be completed in -deficient heart. These findings indicate that Srsf5-regulated alternative splicing plays a critical role during heart development.
富含丝氨酸/精氨酸的（SR）剪接因子家族在mRNA剪接激活、抑制、输出、稳定和翻译中发挥重要作用。SR剪接因子5（SRSF5）是一种葡萄糖诱导蛋白，可促进肿瘤细胞生长。然而，SRSF5在组织发育和疾病中的功能作用仍不清楚。在此，使用CRISPR-Cas9技术构建了基因敲除小鼠。突变小鼠在围产期致死，并表现出心脏功能障碍，心室心肌致密化不全。在收缩期，基因敲除小鼠的左心室内径和容积增加。基因敲除小鼠有异常的心电图模式，提示轻度房室传导阻滞。从机制上讲，Srsf5促进了Myom1（肌间蛋白-1）的可变剪接，Myom1是一种将肌球蛋白丝与肌节M线交联的蛋白质。在基因敲除的心脏中，Myom1胚胎型和成年型异构体之间的转换无法完成。这些发现表明，Srsf5调控的可变剪接在心脏发育过程中起关键作用。
