title: Canonical wnt signaling regulates atrioventricular junction programming and electrophysiological properties.
abstract: BACKGROUND
  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.
  
  
  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 pre-excitation may require both morphological patterning defects, as well as myocardial lineage reprogramming, to allow robust conduction across accessory pathway tissue.
authors.affiliation: From the Department of Medicine, Cardiovascular Division (B.S.G., A.C., H.A., S.R.), and Department of Developmental Biology (B.S.G., A.C., H.A., S.R.), Washington University School of Medicine, St. Louis, MO; Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland (T.V., K.B.); Department of Anatomy, Embryology, and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (V.M.C.); and Department of Biomedical Engineering, Washington University, St. Louis, MO (I.R.E., B.J.B., S.R.).
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Gillers
authors.affiliation: From the Department of Medicine, Cardiovascular Division (B.S.G., A.C., H.A., S.R.), and Department of Developmental Biology (B.S.G., A.C., H.A., S.R.), Washington University School of Medicine, St. Louis, MO; Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland (T.V., K.B.); Department of Anatomy, Embryology, and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (V.M.C.); and Department of Biomedical Engineering, Washington University, St. Louis, MO (I.R.E., B.J.B., S.R.).
authors.forename: Aditi
authors.initials: A
authors.lastname: Chiplunkar
authors.affiliation: From the Department of Medicine, Cardiovascular Division (B.S.G., A.C., H.A., S.R.), and Department of Developmental Biology (B.S.G., A.C., H.A., S.R.), Washington University School of Medicine, St. Louis, MO; Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland (T.V., K.B.); Department of Anatomy, Embryology, and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (V.M.C.); and Department of Biomedical Engineering, Washington University, St. Louis, MO (I.R.E., B.J.B., S.R.).
authors.forename: Haytham
authors.initials: H
authors.lastname: Aly
authors.affiliation: From the Department of Medicine, Cardiovascular Division (B.S.G., A.C., H.A., S.R.), and Department of Developmental Biology (B.S.G., A.C., H.A., S.R.), Washington University School of Medicine, St. Louis, MO; Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland (T.V., K.B.); Department of Anatomy, Embryology, and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (V.M.C.); and Department of Biomedical Engineering, Washington University, St. Louis, MO (I.R.E., B.J.B., S.R.).
authors.forename: Tomas
authors.initials: T
authors.lastname: Valenta
authors.affiliation: From the Department of Medicine, Cardiovascular Division (B.S.G., A.C., H.A., S.R.), and Department of Developmental Biology (B.S.G., A.C., H.A., S.R.), Washington University School of Medicine, St. Louis, MO; Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland (T.V., K.B.); Department of Anatomy, Embryology, and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (V.M.C.); and Department of Biomedical Engineering, Washington University, St. Louis, MO (I.R.E., B.J.B., S.R.).
authors.forename: Konrad
authors.initials: K
authors.lastname: Basler
authors.affiliation: From the Department of Medicine, Cardiovascular Division (B.S.G., A.C., H.A., S.R.), and Department of Developmental Biology (B.S.G., A.C., H.A., S.R.), Washington University School of Medicine, St. Louis, MO; Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland (T.V., K.B.); Department of Anatomy, Embryology, and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (V.M.C.); and Department of Biomedical Engineering, Washington University, St. Louis, MO (I.R.E., B.J.B., S.R.).
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Christoffels
authors.affiliation: From the Department of Medicine, Cardiovascular Division (B.S.G., A.C., H.A., S.R.), and Department of Developmental Biology (B.S.G., A.C., H.A., S.R.), Washington University School of Medicine, St. Louis, MO; Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland (T.V., K.B.); Department of Anatomy, Embryology, and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (V.M.C.); and Department of Biomedical Engineering, Washington University, St. Louis, MO (I.R.E., B.J.B., S.R.).
authors.forename: Igor R
authors.initials: IR
authors.lastname: Efimov
authors.affiliation: From the Department of Medicine, Cardiovascular Division (B.S.G., A.C., H.A., S.R.), and Department of Developmental Biology (B.S.G., A.C., H.A., S.R.), Washington University School of Medicine, St. Louis, MO; Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland (T.V., K.B.); Department of Anatomy, Embryology, and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (V.M.C.); and Department of Biomedical Engineering, Washington University, St. Louis, MO (I.R.E., B.J.B., S.R.).
authors.forename: Bastiaan J
authors.initials: BJ
authors.lastname: Boukens
authors.affiliation: From the Department of Medicine, Cardiovascular Division (B.S.G., A.C., H.A., S.R.), and Department of Developmental Biology (B.S.G., A.C., H.A., S.R.), Washington University School of Medicine, St. Louis, MO; Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland (T.V., K.B.); Department of Anatomy, Embryology, and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (V.M.C.); and Department of Biomedical Engineering, Washington University, St. Louis, MO (I.R.E., B.J.B., S.R.). Stacey.rentschler@wustl.edu.
authors.forename: Stacey
authors.initials: S
authors.lastname: Rentschler
mesh_terms: D000818:Animals; D006325:Heart Atria / Q000196:embryology / Q000378:metabolism* / Q000503:physiopathology; D006329:Heart Conduction System / Q000196:embryology / Q000378:metabolism* / Q000503:physiopathology; D006352:Heart Ventricles / Q000196:embryology / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000378:metabolism; D018785:Tricuspid Atresia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; D051880:Receptors, Notch; D020825:T-Box Domain Proteins; C491460:Tbx3 protein, mouse; D051176:beta Catenin
keywords: Notch signaling pathway; Wnt signaling pathway; arrhythmias, cardiac; arrhythmogenic cardiomyopathy; septal defects; tricuspid atresia; ventricular pre-excitation