Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.
PLoS One. 2013 May 14;8(5):e63265. doi: 10.1371/journal.pone.0063265. Print 2013.
The canonical Wnt/β-catenin signaling pathway plays a crucial role in the maintenance of the balance between proliferation and differentiation throughout embryogenesis and tissue homeostasis. β-Catenin, encoded by the Ctnnb1 gene, mediates an intracellular signaling cascade activated by Wnt. It also plays an important role in the maintenance of various types of stem cells including adult stem cells and cancer stem cells. However, it is unclear if β-catenin is required for the derivation of mouse embryo-derived stem cells. Here, we established β-catenin-deficient (β-cat(Δ/Δ)) mouse embryo-derived stem cells and showed that β-catenin is not essential for acquiring self-renewal potential in the derivation of mouse embryonic stem cells (ESCs). However, teratomas formed from embryo-derived β-cat(Δ/Δ) ESCs were immature germ cell tumors without multilineage differentiated cell types. Re-expression of functional β-catenin eliminated their neoplastic, transformed phenotype and restored pluripotency, thereby rescuing the mutant ESCs. Our findings demonstrate that β-catenin has pleiotropic effects in ESCs; it is required for the differentiation of ESCs and prevents them from acquiring tumorigenic character. These results highlight β-catenin as the gatekeeper in differentiation and tumorigenesis in ESCs.
经典的 Wnt/β-连环蛋白信号通路在胚胎发生和组织稳态过程中维持增殖和分化之间的平衡中起着至关重要的作用。β-连环蛋白由 Ctnnb1 基因编码，介导由 Wnt 激活的细胞内信号级联反应。它在维持各种类型的干细胞（包括成体干细胞和癌症干细胞）中也起着重要作用。然而，目前尚不清楚β-连环蛋白是否是从鼠胚胎衍生的干细胞中获得的必需条件。在这里，我们建立了β-连环蛋白缺陷（β-cat(Δ/Δ)）的鼠胚胎衍生的干细胞，并表明β-连环蛋白对于在鼠胚胎干细胞（ESCs）的衍生中获得自我更新潜能不是必需的。然而，源自胚胎衍生的β-cat(Δ/Δ) ESCs 的畸胎瘤是不成熟的生殖细胞瘤，没有多能分化细胞类型。功能性β-连环蛋白的重新表达消除了它们的肿瘤、转化表型，并恢复了多能性，从而挽救了突变的 ESCs。我们的研究结果表明β-连环蛋白在 ESCs 中有多种作用；它是 ESCs 分化所必需的，并防止它们获得致瘤特征。这些结果突出了β-连环蛋白作为 ESCs 中分化和肿瘤发生的守门员。
