Canonical Wnt signaling regulates atrioventricular junction programming and electrophysiological properties

Benjamin S. Gillers, Aditi Chiplunkar, Haytham Aly, Tomas Valenta, Konrad Basler, Vincent M. Christoffels, Igor R. Efimov, Bastiaan J. Boukens, Stacey Rentschler

Research output: Contribution to journalArticlepeer-review

65 Scopus citations


Rationale: Proper patterning of the atrioventricular canal (AVC) is essential for delay of electrical impulses between atria and ventricles, and defects in AVC maturation can result in congenital heart disease. Objective: To determine the role of canonical Wnt signaling in the myocardium during AVC development. Methods and Results: We used a novel allele of β-catenin that preserves β-catenin's cell adhesive functions but disrupts canonical Wnt signaling, allowing us to probe the effects of Wnt loss of function independently. We show that the loss of canonical Wnt signaling in the myocardium results in tricuspid atresia with hypoplastic right ventricle associated with the loss of AVC myocardium. In contrast, ectopic activation of Wnt signaling was sufficient to induce formation of ectopic AV junction-like tissue as assessed by morphology, gene expression, and electrophysiological criteria. Aberrant AVC development can lead to ventricular pre-excitation, a characteristic feature of Wolff-Parkinson-White syndrome. We demonstrate that postnatal activation of Notch signaling downregulates canonical Wnt targets within the AV junction. Stabilization of β-catenin protein levels can rescue Notch-mediated ventricular pre-excitation and dysregulated ion channel gene expression. Conclusions: Our data demonstrate that myocardial canonical Wnt signaling is an important regulator of AVC maturation and electric programming upstream of Tbx3. Our data further suggest that ventricular preexcitation may require both morphological patterning defects, as well as myocardial lineage reprogramming, to allow robust conduction across accessory pathway tissue.

Original languageEnglish
Pages (from-to)398-406
Number of pages9
JournalCirculation research
Issue number3
StatePublished - Nov 6 2014


  • Arrhythmias
  • Arrhythmogenic cardiomyopathy
  • Cardiac
  • Notch signaling pathway
  • Septal defects
  • Tricuspid atresia
  • Ventricular pre-excitation
  • Wnt signaling pathway


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