Canonical wnt signaling regulates atrioventricular junction programming and electrophysiological properties.
Canonical wnt signaling regulates atrioventricular junction programming and electrophysiological properties.
复制标题
典型的Wnt信号传导调节房屋连接编程和电生理特性。
DOI：
10.1161/circresaha.116.304731
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发表时间：
2015-01-30
影响因子：
20.1
通讯作者：
Rentschler S
中科院分区：
文献类型：
--
作者：
Gillers BS;Chiplunkar A;Aly H;Valenta T;Basler K;Christoffels VM;Efimov IR;Boukens BJ;Rentschler S
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 utilized 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 loss of canonical Wnt signaling in the myocardium results in tricuspid atresia with hypoplastic right ventricle associated with 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 electrophysiologic criteria. Aberrant AVC development can lead to ventricular preexcitation, 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 preexcitation and dysregulated ion channel gene expression. Our data demonstrate that myocardial canonical Wnt signaling is an important regulator of AVC maturation and electrical programming upstream of Tbx3. Our data further suggests that ventricular preexcitation may require both morphologic patterning defects, as well as myocardial lineage reprogramming, to allow robust conduction across accessory pathway tissue.
