β-Catenin-Mediated Signaling and Cell Adhesion in Postgastrulation Mouse Embryos
β-Catenin-Mediated Signaling and Cell Adhesion in Postgastrulation Mouse Embryos
复制标题
DOI：
10.1002/dvdy.22075
复制
发表时间：
2010-01-01
影响因子：
2.5
通讯作者：
Kemler, Rolf
中科院分区：
文献类型：
--
作者：
Hierholzer, Andreas;Kemler, Rolf
β-连环蛋白在多细胞生物的发育过程中起着两个主要作用。它是典型 Wnt 信号级联的下游效应子，参与许多发育过程和肿瘤形成。此外，它与经典的钙粘蛋白相关，并且是粘附连接的正确组装和功能所必需的。 β-连环蛋白功能丧失突变体表现出早期原肠胚形成致死性。为了解决 β-连环蛋白在原肠胚形成后阶段的作用并克服早期胚胎致死性，我们使用新建立的小鼠品系 Cdx1::Cre 进行了条件基因靶向。通过这种方法，在胚胎第 8 天的原肠胚形成过程（三个胚层建立）之后，整个后胚胎中的 β-连环蛋白被耗尽。我们观察到暂时分离的信号传导和粘附缺陷。在早期事件中，已知的 Wnt/β-连环蛋白靶标在轴旁中胚层中下调。此外，分割过程的关键参与者 Fgf8 和 Wnt3a 在神经外胚层 (NE) 中下调。外源 Fgf 可以挽救突变体胚胎中的 Wnt3a 表达，抑制野生型胚胎中的 Fgf 信号传导会导致 Wnt3a 下调。基于这些结果，我们假设 NE 中存在自动调节反馈环，其中 Fgf8 调节 Wnt3a，而 Wnt3a 又通过 β-连环蛋白维持 Fgf8 表达。在后期阶段，β-连环蛋白的缺乏导致进行性后部崩解。我们发现β-连环蛋白是N-钙粘蛋白在神经外胚层细胞膜上正确定位所必需的，并且它的缺失会导致神经管解体。发展动力学 239:191-199, 2010。(C) 2009 Wiley-Liss, Inc.
beta-Catenin plays two major roles during the development of multicellular organisms. It is the downstream effector of the canonical Wnt signaling cascade, which is involved in many developmental processes and in tumor formation. Additionally, it is linked to classic cadherins and is required for the correct assembly and function of adherens junctions. beta-Catenin loss of function mutants show early gastrulation lethality. To address the role of beta-catenin in postgastrulation stages and to overcome the early embryonic lethality, we performed conditional gene targeting, using Cdx1::Cre, a newly established mouse line. By this approach, beta-catenin was depleted in the entire posterior embryo after the gastrulation process at embryonic day 8.0, when the three germ layers were established. We observed defects in signaling and adhesion which are temporarily separated. At an early event, known targets of Wnt/beta-catenin are down-regulated in the paraxial mesoderm. Moreover, Fgf8 and Wnt3a, the key players of the segmentation process, are down-regulated in the neural ectoderm (NE). Wnt3a expression was rescued in mutant embryos by exogenous Fgf and inhibition of Fgf signaling in wild-type embryos resulted in Wnt3a down-regulation. Based on these results, we assume the existence of an autoregulatory feedback loop in the NE where Fgf8 regulates Wnt3a, which in turn, by means of beta-catenin, maintains Fgf8 expression. In later stages, the lack of beta-catenin caused a progressive posterior disintegration. We found that beta-catenin is required for the correct localization of N-cadherin at the membrane of neural ectodermal cells and that its absence causes a disintegration of the neural tube. Developmental Dynamics 239:191-199, 2010. (C) 2009 Wiley-Liss, Inc.