
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.08.29.610377
preprint
1
Article
Coordinated Tbx3 / Tbx5 transcriptional control of the adult ventricular conduction system
Burnicka-Turek Ozanna http://orcid.org/0000-0002-3770-4314

Trampel Katy A.
Laforest Brigitte http://orcid.org/0000-0001-6919-8922

Broman Michael T.
Khan Zoheb
Rytkin Eric
Li Binjie
Schaffer Ella
Gadek Margaret
Shen Kaitlyn M.
Efimov Igor R. http://orcid.org/0000-0002-1483-5039

Moskowitz Ivan P. http://orcid.org/0000-0003-0014-4963

30 8 2024
2024.08.29.610377https://creativecommons.org/publicdomain/zero/1.0/ To the extent possible under law, the person who associated CC0 with this work has waived all copyright and related or neighboring rights to this work.
http://biorxiv.org/lookup/doi/10.1101/2024.08.29.610377
nihpp-2024.08.29.610377.pdf
Abstract

The cardiac conduction system (CCS) orchestrates the electrical impulses that enable coordinated contraction of the cardiac chambers. The T-box transcription factors TBX3 and TBX5 are required for cardiac conduction system development and associated with overlapping and distinct human cardiac conduction system diseases. We evaluated the coordinated role of Tbx3 and Tbx5 in the murine ventricular conduction system (VCS). We engineered a compound Tbx3:Tbx5 conditional knockout allele for both genes located in cis on mouse chromosome 5. Conditional deletion of both T-box transcriptional factors in the ventricular conduction system, using the VCS-specific Mink:Cre, caused loss of VCS function and molecular identity. Combined Tbx3 and Tbx5 deficiency in the adult VCS led to conduction defects, including prolonged PR and QRS intervals and elevated susceptibility to ventricular tachycardia. These electrophysiologic defects occurred prior to detectable alterations in cardiac contractility or histologic morphology, indicative of a primary conduction system defect. Tbx3:Tbx5 double knockout VCS cardiomyocytes revealed a transcriptional shift towards non-CCS-specialized working myocardium, suggesting reprogramming of their cellular identity. Furthermore, optical mapping revealed a loss of VCS-specific conduction system propagation. Collectively, these findings indicate that Tbx3 and Tbx5 coordinate to control VCS molecular fate and function, with implications for understanding cardiac conduction disorders in humans.
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pmc
