Regulation of cell proliferation by Wnt signaling and apical-basal polarity in lung

在本研究中，我们旨在阐明Wnt信号介导的肺分支形态发生机制。我们已经建立了肺上皮细胞的三维培养系统。利用这一点，我们用β-连环蛋白途径激动剂CHIR99021或转导表达Wnt2的慢病毒处理上皮细胞，Wnt2是β-连环蛋白依赖途径的典型配体。Chir或Wnt2促进分枝形态发生。β-连环蛋白途径的激活通过促进根尖和根尖膜上的非典型蛋白酪氨酸酶(APKcheeta)的定位来促进根尖收缩。此外，在分枝形态发生和顶端收缩方面，一种蛋白酪氨酸酶抑制剂表现出缺陷。综上所述，我们发现β-连环蛋白途径维持着远端的祖细胞，并且是分支形态发生所必需的，这是通过顶端靶向的蛋白激酶和顶端收缩所证实的。

In this study, we aim to elucidate the mechanism for lung branching morphogenesis which is mediated by Wnt signaling. We have already generated three dimensional culture system of lung epithelium. By using this, we treated the epithelium with CHIR99021, an agonist for beta-catenin pathway or transduced lentiviruses that express Wnt2, a typical ligand for beta-catenin dependent pathway. CHIR or Wnt2 promoted branching morphogenesis. Activation of beta-catenin pathway promoted apical constriction provably through enhanced localization of atypical PKCzeta (aPKCzeta), a critical regulator of apical and basal polarity, to apical membrane. In addition, aPKCzeta inhibitor showed the defect in branching morphogenesis and apical constriction. In conclusion, we found that beta-catenin pathway maintains distal progenitor and is required for branching morphogenesis provably through apical targeting of aPKCzeta and apical constriction.