# Etv1 is an Essential Regulator of Fast Conduction Tissues in the Heart

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $423,750

## Abstract

PROJECT SUMMARY
Rapid impulse propagation through the atria and ventricular conduction system (VCS) is critical for normal
cardiac activation and contractility. Heritable and acquired syndromes affecting conduction velocity in these
tissues account for a significant burden of arrhythmic disease and are a major cause of morbidity and
mortality. Unfortunately, no therapeutic options exist for improving atrial and VCS conduction due to poor
understanding of the gene regulatory networks. In order to identify essential regulators of the fast conduction
gene program, we made use of a previous observation that Neuregulin-1 (NRG1) is the key mediator of VCS
specification. Using a signal transduction and VCS transcriptional profiling screen, we discovered that NRG1
mediates fast conduction in the heart through the Ras-MAPK-RSK/MSK signaling pathway and the
transcription factor ETV1. ETV1 is a member of the Pea3 group of E-twenty-six (ets) family transcription
factors that regulates specification and electrophysiological modulation of neuronal cell types. We now present
data demonstrating a critical role of ETV1 in establishing and maintaining the fast conduction gene program in
the heart. ETV1 is highly expressed in the atrial pectinated myocardium and VCS, where it up-regulates the
expression of key cardiac conduction genes, Nkx2-5, Scn5a (Nav1.5), and Gja5 (Cx40). Consequently, Etv1
KO mice exhibit conduction slowing in the atria and VCS with a subset displaying frank bundle branch block.
Patch clamp experiments demonstrated that the normal biophysical differences in the sodium current
between atrial, VCS, and ventricular myocytes were lost in Etv1 KO mice, suggesting that ETV1 regulates
additional modifiers of the cardiac sodium current beyond Scn5a. Etv1 KO mice also displayed VCS
hypoplasia with a proportion showing absence of the right bundle branch (RBB), mirroring the defects seen in
NKX2-5 haploinsufficient mice and patients. Analysis of the NKX2-5 promoter identified a highly conserved
ets-binding cluster that upon deletion using CRISPR-Cas9 in vivo recapitulated failure of RBB formation. We
performed PheWAS analysis and found an association between an ETV1 sequence variant and bundle branch
blocks in humans. To further explore the role of ETV1 as a transcriptional regulator of the fast conduction
phenotype, we propose the following specific aims: i) determine the mechanism by which ETV1 regulates the
unique biophysical properties of the sodium current in atrial and Purkinje myocytes, ii) study the functional role of
ETV1 in cardiac conduction and arrhythmogenesis in the adult heart, and iii) elucidate the molecular basis of
bundle branch block in carriers of the ETV1 sequence variant and in Etv1 KO mice.

## Key facts

- **NIH application ID:** 10122976
- **Project number:** 5R01HL132073-05
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** David S Park
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $423,750
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10122976

## Citation

> US National Institutes of Health, RePORTER application 10122976, Etv1 is an Essential Regulator of Fast Conduction Tissues in the Heart (5R01HL132073-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10122976. Licensed CC0.

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