Apc modulates embryonic stem-cell differentiation by controlling the dosage of β-catenin signaling
Apc modulates embryonic stem-cell differentiation by controlling the dosage of β-catenin signaling
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DOI：
10.1038/ng1045
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发表时间：
2002-12-01
期刊：
影响因子：
30.8
通讯作者：
Fodde, R
中科院分区：
文献类型：
--
作者：
Kielman, MF;Rindapää, M;Fodde, R
Wnt信号转导通路诱导膜结合的β-连环蛋白(Catnb)的核转位，在决定细胞命运中起着关键作用。对这一信号进行严格的躯体调控是必不可少的，因为不受控制的β-连环蛋白的核积累可能会导致成年生物体的发育缺陷和肿瘤发生。腺瘤性息肉病结肠基因(APC)是Wnt途径的主要控制者，对防止多种组织和器官的肿瘤发生至关重要。在这里，我们研究了不同的APC突变对小鼠胚胎干细胞分化潜能的影响。我们提供了遗传和分子证据，证明ES细胞分化为三个胚层的能力和敏感性受到特定APC突变导致的β-连环素剂量增加的抑制。这些缺陷包括APC等位基因在β-连环蛋白调控方面完全缺乏的严重分化障碍，以及更具特异性的神经外胚层、背侧中胚层和内胚层缺陷。因此，Catnb中有针对性的致癌突变也会影响ES细胞的分化潜能。野生型和APC突变畸胎瘤的表达谱在分子水平上支持分化缺陷，并定位了大量下游结构和调控基因。嵌合实验表明，这种效应是细胞自主的。我们的结果表明，APC/β-连环蛋白信号通路的结构性激活导致组织内稳态的分化缺陷，并可能是结肠和其他自我更新组织肿瘤发生的基础。
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.