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?-catenin functions pleiotropically in differentiation and tumorigenesis in mouse embryo-derived stem cells.

ABSTRACT: The canonical Wnt/?-catenin signaling pathway plays a crucial role in the maintenance of the balance between proliferation and differentiation throughout embryogenesis and tissue homeostasis. ?-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 ?-catenin is required for the derivation of mouse embryo-derived stem cells. Here, we established ?-catenin-deficient (?-cat(?/?)) mouse embryo-derived stem cells and showed that ?-catenin is not essential for acquiring self-renewal potential in the derivation of mouse embryonic stem cells (ESCs). However, teratomas formed from embryo-derived ?-cat(?/?) ESCs were immature germ cell tumors without multilineage differentiated cell types. Re-expression of functional ?-catenin eliminated their neoplastic, transformed phenotype and restored pluripotency, thereby rescuing the mutant ESCs. Our findings demonstrate that ?-catenin has pleiotropic effects in ESCs; it is required for the differentiation of ESCs and prevents them from acquiring tumorigenic character. These results highlight ?-catenin as the gatekeeper in differentiation and tumorigenesis in ESCs.

SUBMITTER: Okumura N

PROVIDER: S-EPMC3653942 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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β-catenin functions pleiotropically in differentiation and tumorigenesis in mouse embryo-derived stem cells.

Okumura Noriko N Akutsu Hidenori H Sugawara Tohru T Miura Takumi T Takezawa Youki Y Hosoda Akihiro A Yoshida Keiichi K Ichida Justin K JK Yamada Mitsutoshi M Hamatani Toshio T Kuji Naoaki N Miyado Kenji K Yoshimura Yasunori Y Umezawa Akihiro A

PloS one 20130514 5

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 ...[more]

PMID: 23691006

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Project description:Osteoporosis is a widespread bone metabolic disease characterized by reduced bone mass and bone microstructure deterioration. Ribonucleotide reductase M2 (RRM2) is a key enzyme in DNA synthesis and repair. The present study investigated the effect of RRM2 on osteogenesis of mouse embryo fibroblasts (MEFs) and its molecular mechanism. Bioinformatics analysis revealed that RRM2 expression was increased during osteogenesis of MEFs triggered by bone morphogenetic protein 9. Subsequently, MEFs were used as a mesenchymal stem cell model and osteogenic inducing medium was used to induce osteogenic differentiation. RRM2 protein expression was measured by western blotting during osteogenic differentiation induction of MEFs. RRM2 levels in MEFs were upregulated and downregulated by RRM2-overexpressing recombinant adenovirus and small interfering RNA-RRM2, respectively. Bone formation markers (RUNX family transcription factor 2, osterix, distal-less homeobox 5, collagen type I α1 chain, osteopontin and osteocalcin) were detected by reverse transcription-quantitative (RT-q) PCR and alkaline phosphatase (ALP) and Alizarin Red S staining were examined. The protein expression levels of β-catenin and the ratio of phosphorylated (p-)GSK-3β to GSK-3β were detected by western blotting and the RNA expression of downstream related target genes (β-catenin, axis inhibition protein 2 (AXIN2), transcription factor 7 like 2, lymphoid enhancer binding factor 1, c-MYC and Cyclin D1) in the Wnt/β-catenin signaling pathway was measured by RT-qPCR. RRM2 protein expression increased as the osteogenic differentiation induction period was extended. RRM2 overexpression increased osteogenic marker RNA expression, ALP activity, bone mineralization, the protein expression levels of β-catenin, the ratio of p-GSK-3β to GSK-3β and the RNA expression of downstream related target genes in the Wnt/β-catenin signaling pathway, whereas RRM2 knockdown had the opposite effect. The findings of the present study revealed that RRM2 overexpression enhanced osteogenic differentiation, while RRM2 knockdown reduced osteogenic differentiation. RRM2 may regulate osteogenic differentiation of MEFs via the canonical Wnt/β-catenin signaling pathway, providing a possible therapeutic target for osteoporosis.

Dataset Information

?-catenin functions pleiotropically in differentiation and tumorigenesis in mouse embryo-derived stem cells.

Publications

β-catenin functions pleiotropically in differentiation and tumorigenesis in mouse embryo-derived stem cells.

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