Work

Splicing Factor SRSF5 Deletion Disrupts Alternative Splicing and Causes Noncompaction of Ventricular Myocardium

Year: 2021

Type: article

Abstract: Serine/arginine rich (SR) family of splicing factors serve important roles in mRNA splicing activation, splicing repression, export, stabilization, and translation. SR-splicing factor 5 (SRSF5) had been reported to be a glucose-inducible protein that promotes tumor cell growth via alternative splicing of CCAR1, a master of cell cycle arrest and apoptosis. However, the functional role of SRSF5 in tissue development and disease is unknown. Here we generated SRSF5 knockout (Srsf5-/-) mice using CRISPR-Cas 9 technology. Mutant mice were perinatally lethal and exhibited cardiac dysfunction with noncompaction of ventricular myocardium. Systemic loss of SRSF5 results in cardiac dysfunction. The left ventricular internal diameter as well as the left ventricular volume were increased in Srsf5-/- mice during systole. Null mice had abnormal electrocardiogram patterns where the QRS wave amplitude and heart rate were extremely lower. The PR intervals and QTc intervals of mutant mice heart were strikingly prolonged, implying light atrioventricular block as well as a tendency to induce ventricular arrhythmias. Mechanically, we observed SRSF5 promoted the alterative splicing of MYOM1, a protein that crosslinks myosin filaments to sarcomeric M-line and maintained structural integrity during contraction. The isoform switch of MYOM1 was unable to be completed in SRSF5-deficient cardiac, and more embryonic MYOM1 isoform was retained. Thus, we concluded that SRSF5-regulated alternative splicing played a critical role during heart development.

Source: iScience

DOI: 10.1016/j.isci.2021.103097