Gillers Benjamin S, Chiplunkar Aditi, Aly Haytham, Valenta Tomas, Basler Konrad, Christoffels Vincent M, Efimov Igor R, Boukens Bastiaan J, Rentschler Stacey
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.).
Circ Res. 2015 Jan 30;116(3):398-406. doi: 10.1161/CIRCRESAHA.116.304731. Epub 2014 Nov 6.
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.
To determine the role of canonical Wnt signaling in the myocardium during AVC development.
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.
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.
房室管（AVC）的正常模式对于心房和心室之间电冲动的延迟至关重要，AVC成熟缺陷可导致先天性心脏病。
确定经典Wnt信号通路在AVC发育过程中心肌中的作用。
我们使用了一种新型的β-连环蛋白等位基因，该等位基因保留了β-连环蛋白的细胞黏附功能，但破坏了经典Wnt信号通路，使我们能够独立探究Wnt功能丧失的影响。我们发现心肌中经典Wnt信号通路的丧失会导致三尖瓣闭锁，并伴有与AVC心肌丧失相关的右心室发育不全。相比之下，通过形态学、基因表达和电生理学标准评估，Wnt信号通路的异位激活足以诱导异位房室结样组织的形成。异常的AVC发育可导致心室预激，这是 Wolff-Parkinson-White综合征的一个特征。我们证明出生后Notch信号通路的激活会下调房室结内的经典Wnt靶标。β-连环蛋白蛋白水平的稳定可以挽救Notch介导的心室预激和离子通道基因表达失调。
我们的数据表明，心肌中的经典Wnt信号通路是Tbx3上游AVC成熟和电编程的重要调节因子。我们的数据进一步表明，心室预激可能需要形态模式缺陷以及心肌谱系重编程，才能使电流在附加通路组织中强劲传导。
