# Nr2f1a promotes atrial maintenance and ventricular growth in the embryonic zebrafish heart

> **NIH NIH F31** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $40,440

## Abstract

Project Summary/Abstract
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.

## Key facts

- **NIH application ID:** 10385751
- **Project number:** 5F31HL152600-03
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Kendall Martin
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $40,440
- **Award type:** 5
- **Project period:** 2020-04-09 → 2023-04-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10385751

## Citation

> US National Institutes of Health, RePORTER application 10385751, Nr2f1a promotes atrial maintenance and ventricular growth in the embryonic zebrafish heart (5F31HL152600-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10385751. Licensed CC0.

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