de Jaime Soguero, AnchelAulicino, Francesco, 1987-Ertaylan, GokhanGriego, AnnaCerrato, AnielloTallam, Aravinddel Sol, AntonioCosma, Maria Pia, 1970-Lluis Vinas, Frederic2018-07-042018-07-042017De Jaime-Soguero A, Aulicino F, Ertaylan G, Griego A, Cerrato A, Tallam A et al. Wnt/Tcf1 pathway restricts embryonic stem cell cycle through activation of the Ink4/Arf locus. PLoS Genet. 2017 Mar 27;13(3):e1006682. DOI: 10.1371/journal.pgen.10066821553-7390http://hdl.handle.net/10230/35028Understanding 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.application/pdfeng© 2017 De Jaime-Soguero et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1371/journal.pgen.1006682Cell cycle inhibitorsCell divisionCell proliferationCell stainingGene expression regulationG1 phaseCloninginfo:eu-repo/semantics/openAccess