TBX5 drives Scn5a expression to regulate cardiac conduction system function

J Clin Invest. 2012 Jul;122(7):2509-18. doi: 10.1172/JCI62617. Epub 2012 Jun 25.

Abstract

Cardiac conduction system (CCS) disease, which results in disrupted conduction and impaired cardiac rhythm, is common with significant morbidity and mortality. Current treatment options are limited, and rational efforts to develop cell-based and regenerative therapies require knowledge of the molecular networks that establish and maintain CCS function. Recent genome-wide association studies (GWAS) have identified numerous loci associated with adult human CCS function, including TBX5 and SCN5A. We hypothesized that TBX5, a critical developmental transcription factor, regulates transcriptional networks required for mature CCS function. We found that deletion of Tbx5 from the mature murine ventricular conduction system (VCS), including the AV bundle and bundle branches, resulted in severe VCS functional consequences, including loss of fast conduction, arrhythmias, and sudden death. Ventricular contractile function and the VCS fate map remained unchanged in VCS-specific Tbx5 knockouts. However, key mediators of fast conduction, including Nav1.5, which is encoded by Scn5a, and connexin 40 (Cx40), demonstrated Tbx5-dependent expression in the VCS. We identified a TBX5-responsive enhancer downstream of Scn5a sufficient to drive VCS expression in vivo, dependent on canonical T-box binding sites. Our results establish a direct molecular link between Tbx5 and Scn5a and elucidate a hierarchy between human GWAS loci that affects function of the mature VCS, establishing a paradigm for understanding the molecular pathology of CCS disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arrhythmias, Cardiac / diagnostic imaging
  • Arrhythmias, Cardiac / genetics
  • Arrhythmias, Cardiac / physiopathology
  • Binding Sites
  • Connexins / genetics
  • Connexins / metabolism
  • Electrocardiography
  • Enhancer Elements, Genetic
  • Gene Expression Regulation*
  • Gene Knockout Techniques
  • Heart Conduction System / metabolism
  • Heart Conduction System / pathology
  • Heart Conduction System / physiopathology*
  • Heart Ventricles / diagnostic imaging
  • Heart Ventricles / metabolism
  • Heart Ventricles / physiopathology
  • Mice
  • Mice, Transgenic
  • Myocardial Contraction
  • NAV1.5 Voltage-Gated Sodium Channel
  • Sodium Channels / genetics
  • Sodium Channels / metabolism*
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism
  • T-Box Domain Proteins / physiology*
  • Ultrasonography

Substances

  • Connexins
  • NAV1.5 Voltage-Gated Sodium Channel
  • SCN5A protein, human
  • Scn5a protein, mouse
  • Sodium Channels
  • T-Box Domain Proteins
  • T-box transcription factor 5
  • connexin 40