SRSF3 is a key regulator of epicardial formation

The epicardium is a fundamental regulator of cardiac development, functioning to secrete essential growth factors and to produce epicardium-derived cells (EPDCs) that contribute most coronary vascular smooth muscle cells and cardiac fibroblasts. The molecular mechanisms that control epicardial formation and proliferation have not been fully elucidated. In this study, we found that the RNA-binding protein SRSF3 is highly expressed in the proepicardium and later in the epicardial layer during heart development. Deletion of Srsf3 from the murine proepicardium using the Tg(Gata5-Cre) or embryonic day (E) 8.5 induction of Wt1CreERT2 led to proliferative arrest and impaired epithelial-to-mesenchymal transition (EMT), which prevented proper formation and function of the epicardial layer. Induction of Srsf3 deletion with the Wt1CreERT2 after the proepicardial stage resulted in impaired EPDC formation and epicardial proliferation at E13.5. Single-cell RNA-sequencing showed SRSF3-depleted epicardial cells were removed by E15.5 and the remaining non-recombined cells became hyperproliferative and compensated for the loss via up-regulation of Srsf3. This research identifies SRSF3 as a master regulator of cellular proliferation in epicardial cells.