MYRF is Essential for Epicardial Development

Myelin Regulatory Factor (MYRF) is a transcription factor previously known for myelination of neurons in the central nervous system. Accumulating evidence has recently implicated MYRF mutations in the pathogenesis of cardiac urogenital syndrome (CUGS), in which patients exhibit a range of cardiac abnormalities, including atrial septal defect (ASD), ventricular septal defect (VSD), and hypoplastic left heart syndrome (HLHS). However, the mechanisms by which MYRF deficiency leads to cardiac anomalies remain poorly defined. Moreover, in part due to the lack of cell-type specific loss-of-function models, it is unclear which cardiac cell types contribute to the defects observed in MYRF-related CUGS. To address these questions, we examined the expression pattern of MYRF in the heart and found that it is most highly expressed in epicardial cells (EPCs) among all cardiac cell types. Importantly, Myrf global knockout (KO) mice displayed impeded epicardial development, with markedly reduced epicardial coverage of the myocardial surface. Furthermore, specifically deleting MYRF in EPCs results in severely degenerated epicardium, dramatically reduced epicardial derived cells (EPDCs), and thin myocardial wall. Conversely, ablating MYRF in cardiomyocytes (CMs) did not lead to any overt cardiac phenotypes, indicating that MYRF is dispensable for the developing CMs. Taken together, our findings suggest that compromised function of MYRF in EPCs may contribute to the pathogenesis of MYRF-related CUGS. To our knowledge, this is the first study to link impaired epicardial development to this disease.