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- Title
Wnt/Tcf1 pathway restricts embryonic stem cell cycle through activation of the Ink4/Arf locus.
- Authors
De Jaime-Soguero, Anchel; Aulicino, Francesco; Ertaylan, Gokhan; Griego, Anna; Cerrato, Aniello; Tallam, Aravind; del Sol, Antonio; Cosma, Maria Pia; Lluis, Frederic
- Abstract
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 naïve pluripotency by holding back differentiation. The canonical Wnt/β-catenin pathway controls mESC pluripotency via the Wnt-effector Tcf3. However, if the activity of the Wnt/β-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 p15Ink4b, p16Ink4a and p19Arf, which mediate the Wnt-dependent anti-proliferative effect in mESCs. Consistently, ablation of β-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.
- Subjects
CELL cycle; CELL proliferation; PLURIPOTENT stem cells; EMBRYONIC stem cells; GENE expression
- Publication
PLoS Genetics, 2017, Vol 13, Issue 3, p1
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.1006682