Kielman Menno F, Rindapää Maaret, Gaspar Claudia, van Poppel Nicole, Breukel Cor, van Leeuwen Sandra, Taketo Makoto Mark, Roberts Scott, Smits Ron, Fodde Riccardo
Center for Human and Clinical Genetics, Leiden University Medical Center, Sylvius Laboratory, Wassenaarseweg 72, 2333 RA Leiden, The Netherlands.
Nat Genet. 2002 Dec;32(4):594-605. doi: 10.1038/ng1045. Epub 2002 Nov 11.
The Wnt signal-transduction pathway induces the nuclear translocation of membrane-bound beta-catenin (Catnb) and has a key role in cell-fate determination. Tight somatic regulation of this signal is essential, as uncontrolled nuclear accumulation of beta-catenin can cause developmental defects and tumorigenesis in the adult organism. The adenomatous polyposis coli gene (APC) is a major controller of the Wnt pathway and is essential to prevent tumorigenesis in a variety of tissues and organs. Here, we have investigated the effect of different mutations in Apc on the differentiation potential of mouse embryonic stem (ES) cells. We provide genetic and molecular evidence that the ability and sensitivity of ES cells to differentiate into the three germ layers is inhibited by increased doses of beta-catenin by specific Apc mutations. These range from a severe differentiation blockade in Apc alleles completely deficient in beta-catenin regulation to more specific neuroectodermal, dorsal mesodermal and endodermal defects in more hypomorphic alleles. Accordingly, a targeted oncogenic mutation in Catnb also affects the differentiation potential of ES cells. Expression profiling of wildtype and Apc-mutated teratomas supports the differentiation defects at the molecular level and pinpoints a large number of downstream structural and regulating genes. Chimeric experiments showed that this effect is cell-autonomous. Our results imply that constitutive activation of the Apc/beta-catenin signaling pathway results in differentiation defects in tissue homeostasis, and possibly underlies tumorigenesis in the colon and other self-renewing tissues.
Wnt信号转导通路可诱导膜结合型β-连环蛋白（Catnb）的核转位，在细胞命运决定中起关键作用。对该信号进行严格的体细胞调控至关重要，因为β-连环蛋白不受控制的核积累可导致成年生物体出现发育缺陷和肿瘤发生。腺瘤性息肉病大肠杆菌基因（APC）是Wnt通路的主要调控因子，对于预防多种组织和器官的肿瘤发生至关重要。在此，我们研究了Apc中不同突变对小鼠胚胎干细胞（ES细胞）分化潜能的影响。我们提供了遗传和分子证据，表明特定的Apc突变导致β-连环蛋白剂量增加会抑制ES细胞分化为三个胚层的能力和敏感性。这些影响范围从完全缺乏β-连环蛋白调控的Apc等位基因中的严重分化阻滞，到更亚效等位基因中更特异性的神经外胚层、背侧中胚层和内胚层缺陷。因此，Catnb中的靶向致癌突变也会影响ES细胞的分化潜能。野生型和Apc突变的畸胎瘤的表达谱分析支持了分子水平上的分化缺陷，并确定了大量下游结构和调控基因。嵌合体实验表明这种效应是细胞自主性的。我们的结果表明，Apc/β-连环蛋白信号通路的组成性激活会导致组织稳态中的分化缺陷，并可能是结肠和其他自我更新组织肿瘤发生的基础。
