Notch signaling regulates murine atrioventricular conduction and the formation of accessory pathways

Abstract

Ventricular preexcitation, which characterizes Wolff-Parkinson-White syndrome, is caused by the presence of accessory pathways that can rapidly conduct electrical impulses from atria to ventricles, without the intrinsic delay characteristic of the atrioventricular (AV) node. Preexcitation is associated with an increased risk of tachyarrhythmia, palpitations, syncope, and sudden death. Although the pathology and electrophysiology of preexcitation syndromes are well characterized, the developmental mechanisms are poorly understood, and few animal models that faithfully recapitulate the human disorder have been described. Here we show that activation of Notch signaling in the developing myocardium of mice can produce fully penetrant accessory pathways and ventricular preexcitation. Conversely, inhibition of Notch signaling in the developing myocardium resulted in a hypoplastic AV node, with specific loss of slow-conducting cells expressing connexin-30.2 (Cx30.2) and a resulting loss of physiologic AV conduction delay. Taken together, our results suggest that Notch regulates the functional maturation of AV canal embryonic myocardium during the development of the specialized conduction system. Our results also show that ventricular preexcitation can arise from inappropriate patterning of the AV canal-derived myocardium.

Myocardin regulates BMP10 expression and is required for heart development

“…Whole-mount immunostaining was performed with monoclonal anti-MLC2v primary antibody (AXXORA) and HRP-conjugated IgG secondary antibody (Cell Signaling), as described (35). High-resolution optical mapping studies were performed on an Olympus BX51WI microscope equipped with a high-speed CMOS camera (MiCAM ULTIMA L; SciMedia Ltd.), as described (36).…”

The formation and function of the cardiac conduction system

“…In mice, Hey1 and Hey2 prevent the expression of Tbx2 in the atrial and ventricular myocardium, respectively, although Hey1 and Hey2 expression is not affected by ectopic Tbx2 or Notch2 overexpression or by Notch2 inactivation (Kokubo et al, 2005;Rutenberg et al, 2006). The inhibition of Notch signalling in mice leads to a hypoplastic AVN and a disrupted AV nodal delay whereas, conversely, myocardial activation of Notch produces accessory pathways and ventricular pre-excitation (Rentschler et al, 2011). Canonical Wnt signalling is also required for correct AVC development and electrical programming.…”

Transcription factor ISL1 is essential for pacemaker development and function

“…SAN cell proliferation continues until shortly before birth (36). A number of signaling pathways, including neuregulin/ErbB, endothelin, and Notch signaling pathways, have been implicated in various aspects of atrioventricular and ventricular conduction system development (37)(38)(39)(40)(41)(42); however, our understanding of signaling pathways regulating proliferation and differentiation of SAN cells and their progenitors is limited.…”