TBX5 drives Scn5a expression to regulate cardiac conduction system function
David E. Arnolds, Fang Liu, John P. Fahrenbach, Gene H. Kim, Kurt J. Schillinger, Scott Smemo, Elizabeth M. McNally, Marcelo A. Nobrega, Vickas V. Patel, Ivan P. Moskowitz
David E. Arnolds, Fang Liu, John P. Fahrenbach, Gene H. Kim, Kurt J. Schillinger, Scott Smemo, Elizabeth M. McNally, Marcelo A. Nobrega, Vickas V. Patel, Ivan P. Moskowitz
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Research Article

TBX5 drives Scn5a expression to regulate cardiac conduction system function

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.

Authors

David E. Arnolds, Fang Liu, John P. Fahrenbach, Gene H. Kim, Kurt J. Schillinger, Scott Smemo, Elizabeth M. McNally, Marcelo A. Nobrega, Vickas V. Patel, Ivan P. Moskowitz

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Figure 2

Conduction slowing and arrhythmias after removal of Tbx5 from the ventricular CCS.

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Conduction slowing and arrhythmias after removal of Tbx5 from the ventri...
(A–J) Conduction system function in Tbx5fl/fl (B and E) and Tbx5minKCreERT2 (C and F–J) mice was evaluated by ambulatory telemetry (B, C, and G–J) and invasive EP studies (E and F). Electroanatomical correlates of ECG and EP recordings are shown in A and D, respectively. la and ra, left and right atria; AVB, AV bundle; AVN and SAN, AV and SA nodes; LBB and RBB, left and right bundle branches. PR and QRS intervals were prolonged during ambulatory telemetry analysis (representative recordings in B and C), and intracardiac recordings (representative recordings in E and F) demonstrated prolongation of AH interval, Hd, and HV interval. Mobitz type II second-degree AV block (G) occurred exclusively in Tbx5minKCreERT2 mice. PVCs (H) were more common in Tbx5minKCreERT2 mice, and ventricular tachycardia (I and J) was observed exclusively in Tbx5minKCreERT2 mice. Boxed area in I is shown at slower scale in J. Scale bars: 50 ms. Arrows in G represent nonconducted p waves. See Table 1 for quantification of ECG and EP intervals.