Grigoryan Tamara, Wend Peter, Klaus Alexandra, Birchmeier Walter
Max-Delbück Center for Molecular Medicine, 13125 Berlin, Germany.
Genes Dev. 2008 Sep 1;22(17):2308-41. doi: 10.1101/gad.1686208.
Wnt signaling is one of a handful of powerful signaling pathways that play crucial roles in the animal life by controlling the genetic programs of embryonic development and adult homeostasis. When disrupted, these signaling pathways cause developmental defects, or diseases, among them cancer. The gateway of the canonical Wnt pathway, which contains >100 genes, is an essential molecule called beta-catenin (Armadillo in Drosophila). Conditional loss- and gain-of-function mutations of beta-catenin in mice provided powerful tools for the functional analysis of canonical Wnt signaling in many tissues and organs. Such studies revealed roles of Wnt signaling that were previously not accessible to genetic analysis due to the early embryonic lethality of conventional beta-catenin knockout mice, as well as the redundancy of Wnt ligands, receptors, and transcription factors. Analysis of conditional beta-catenin loss- and gain-of-function mutant mice demonstrated that canonical Wnt signals control progenitor cell expansion and lineage decisions both in the early embryo and in many organs. Canonical Wnt signaling also plays important roles in the maintenance of various embryonic or adult stem cells, and as recent findings demonstrated, in cancer stem cell types. This has opened new opportunities to model numerous human diseases, which have been associated with deregulated Wnt signaling. Our review summarizes what has been learned from genetic studies of the Wnt pathway by the analysis of conditional beta-catenin loss- and gain-of-function mice.
Wnt信号通路是少数几个强大的信号通路之一，通过控制胚胎发育和成年体内平衡的遗传程序，在动物生命中发挥关键作用。当这些信号通路被破坏时，会导致发育缺陷或疾病，其中包括癌症。经典Wnt通路的门户分子是一种名为β-连环蛋白（果蝇中的犰狳蛋白）的重要分子，该通路包含100多个基因。小鼠中β-连环蛋白的条件性功能丧失和功能获得突变，为在许多组织和器官中对经典Wnt信号进行功能分析提供了强大工具。此类研究揭示了Wnt信号的作用，由于传统β-连环蛋白敲除小鼠的早期胚胎致死性以及Wnt配体、受体和转录因子的冗余性，这些作用以前无法通过遗传分析获得。对条件性β-连环蛋白功能丧失和功能获得突变小鼠的分析表明，经典Wnt信号在早期胚胎和许多器官中控制祖细胞的扩增和谱系决定。经典Wnt信号在维持各种胚胎或成体干细胞以及如最近的研究所表明的在癌症干细胞类型中也发挥重要作用。这为模拟许多与Wnt信号失调相关的人类疾病开辟了新的机会。我们的综述总结了通过分析条件性β-连环蛋白功能丧失和功能获得小鼠，从Wnt通路的遗传研究中学到的知识。
