期刊
PLOS GENETICS
卷 13, 期 3, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1006682
关键词
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资金
- ERC [242630-RERE]
- Ministerio de Economia y Competitividad y FEDER [SAF20112 8580, BFU2014-54717-P, BFU2015-71984ERC]
- Secretaria d 'Universitats i Investigacio del Departament d 'Economia i Coneixement de la Generalitat de Catalunya [2014SGR1137]
- Ministerio de Ciencia e Innovacion FPI
- European Union's Horizon 2020 research and innovation programme [686637]
- Spanish Ministry of Economy and Competitiveness
- Centro de Excelencia Severo Ochoa 2013-2017
- CERCA Programme/Generalitat de Catalunya
- KU Leuven [C14/16/078]
- Luxembourg National Research Fund (FNR)
- ANEMO [4001584/PDR 2012-1]
- Dutch Province of Limburg
- CNR
- ICREA Funding Source: Custom
Understanding the mechanisms regulating cell cycle, proliferation and potency of pluripotent stem cells guarantees their safe use in the clinic. Embryonic stem cells (ESCs) present a fast cell cycle with a short G1 phase. This is due to the lack of expression of cell cycle inhibitors, which ultimately determines naive pluripotency by holding back differentiation. The canonical Wnt/beta-catenin pathway controls mESC pluripotency via the Wnt-effector Tcf3. However, if the activity of the Wnt/beta-catenin controls the cell cycle of mESCs remains unknown. Here we show that the Wnt-effector Tcf1 is recruited to and triggers transcription of the Ink4/Arf tumor suppressor locus. Thereby, the activation of the Wnt pathway, a known mitogenic pathway in somatic tissues, restores G1 phase and drastically reduces proliferation of mESCs without perturbing pluripotency. Tcf1, but not Tcf3, is recruited to a palindromic motif enriched in the promoter of cell cycle repressor genes, such as p15(Ink4b), p16(Ink4a) and p19(Arf), which mediate the Wnt-dependent anti-proliferative effect in mESCs. Consistently, ablation of beta-catenin or Tcf1 expression impairs Wnt-dependent cell cycle regulation. All together, here we showed that Wnt signaling controls mESC pluripotency and proliferation through non-overlapping functions of distinct Tcf factors.
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