Congenital heart defects (CHDs) are the most common type of congenital malformation and the leading cause of birth defect associated infant death. CHDs can affect many different structures within the heart, including the atrial and ventricular septa and outflow tract (OFT). Atrial septal defects (ASDs) are often associated with arrhythmias and conduction defects, which can occur concurrently due to mutations in genes vital for both early development of the cardiac chambers and development of the sinoatrial node (SAN), which houses the pacemaker cells of the heart. While surgical intervention can correct some CHDs, surgery often does not repair associated conduction defects. Furthermore, arrhythmias are the leading cause of morbidity and mortality in adults with CHDs. Mutations in NR2F2, a member of the orphan nuclear hormone receptor transcription factor family, have been associated with multiple types of CHDs, most commonly ASDs but recently ventricular and OFT defects have been reported as well. NR2F2 is specifically expressed in atrial cardiomyocytes (ACs) in both humans and mice, and mouse studies have shown that Nr2f2 is required for atrial development and maintenance; however, the mechanisms by which these proteins function within ACs and how mutations in NR2F2 result in a spectrum of CHDs affecting both the atria and ventricles are not well understood. Recent work from our lab has identified zebrafish Nr2f1a as the functional equivalent of mammalian Nr2f2. Our preliminary data using zebrafish has revealed that in the absence of Nr2f1a there is a progressive ectopic expansion of SAN identity within ACs. Furthermore, integration of RNA-seq and ATAC-seq analysis of isolated ACs suggests that Nr2f1a represses the core SAN gene regulatory network (GRN) by maintaining expression nkx2.5 within ACs.
In Aim 1, we will test the hypothesis that Nr2f1a is required to repress SAN identity by directly maintaining expression of Nkx2.5. Additionally, our preliminary data has revealed a novel requirement for Nr2f1a in ventricular development.
In Aim 2, we will test the hypothesis that Nr2f1a cell non-autonomously promotes ventricular growth. Ultimately, the proposed studies have the potential to illuminate previously unknown molecular and genetic etiology underlying congenital arrhythmias and CHDs affecting both the atria and ventricles associated with NR2F2 mutations found in humans.
Congenital heart defects (CHDs) are the most common type of birth defect and the leading cause of infant morbidity and mortality. Mutations in the transcription factor NR2F2 have been associated with multiple types of CHDs affecting both the atria and ventricles; however, the mechanisms underlying the etiology of this spectrum of CHDs is not understood. The results of this proposal will not only illuminate the genetic and molecular etiology underlying CHDs associated with NR2F2 mutations, but also aid in the generation of novel strategies for the prevention, repair, and maintenance of CHDs.
