CoordinatedTbx3 / Tbx5transcriptional control of the adult ventricular conduction system

Abstract

AbstractThe cardiac conduction system (CCS) orchestrates the electrical impulses that enable coordinated contraction of the cardiac chambers. The T-box transcription factorsTBX3andTBX5are required for cardiac conduction system development and associated with overlapping and distinct human cardiac conduction system diseases. We evaluated the coordinated role ofTbx3andTbx5in the murine ventricular conduction system (VCS). We engineered a compoundTbx3:Tbx5conditional knockout allele for both genes located incison mouse chromosome 5. Conditional deletion of both T-box transcriptional factors in the ventricular conduction system, using the VCS-specificMink:Cre,caused loss of VCS function and molecular identity. CombinedTbx3andTbx5deficiency 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:Tbx5double 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 thatTbx3andTbx5coordinate to control VCS molecular fate and function, with implications for understanding cardiac conduction disorders in humans.