UCSF

With each heartbeat, impulses generated by the sinoatrial node travel through the atria, pause at the atrioventricular node, and proceed to the ventricular conduction system (VCS), also known as the His-Purkinje network. Rapid electrical conduction in the VCS tightly controls spatiotemporal mechanical activation of the ventricles, thereby optimizing pump function. Conduction through the VCS is impaired in several inherited forms of cardiac conduction disorders and associated with increased risk of arrhythmias and heart disease. Although regulation of early specification and patterning of this tissue is becoming better understood, less is known about how transcriptional regulation establishes fast conducting properties of its constituent cells. Using a combination of approaches including mouse genetics, 3D imaging, electrophysiology, cell and molecular biology, we show that the Iroquois homeobox gene 3 is critical for efficient impulse conduction and ventricular activation in mice and zebrafish. Specifically, loss of Irx3 in mice resulted in disruption of the rapid and coordinated spread of ventricular excitation, decreased cellular excitability, and altered intercellular coupling. We detected decreased levels of Cx40 in the conduction axis and ectopic Cx43 expression in the proximal bundle branches. We show that Irx3 directly represses Gja1 (encoding Cx43) transcription and indirectly activates Gja5 (encoding Cx40). Our results reveal a novel role for Irx3 in the regulation of impulse propagation and ventricular conduction system function.