2.50
Hdl Handle:
http://hdl.handle.net/10033/621221
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.
Affiliation:
TwinCore, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
Citation:
Wnt/Tcf1 pathway restricts embryonic stem cell cycle through activation of the Ink4/Arf locus. 2017, 13 (3):e1006682 PLoS Genet.
Journal:
PLoS genetics
Issue Date:
Mar-2017
URI:
http://hdl.handle.net/10033/621221
DOI:
10.1371/journal.pgen.1006682
PubMed ID:
28346462
Type:
Article
Language:
en
ISSN:
1553-7404
Appears in Collections:
publications of the research group biomarker in infection and immunity [[TC] BIOM)

Full metadata record

DC FieldValue Language
dc.contributor.authorDe Jaime-Soguero, Anchelen
dc.contributor.authorAulicino, Francescoen
dc.contributor.authorErtaylan, Gokhanen
dc.contributor.authorGriego, Annaen
dc.contributor.authorCerrato, Anielloen
dc.contributor.authorTallam, Aravinden
dc.contributor.authorDel Sol, Antonioen
dc.contributor.authorCosma, Maria Piaen
dc.contributor.authorLluis, Fredericen
dc.date.accessioned2018-01-03T09:14:00Z-
dc.date.available2018-01-03T09:14:00Z-
dc.date.issued2017-03-
dc.identifier.citationWnt/Tcf1 pathway restricts embryonic stem cell cycle through activation of the Ink4/Arf locus. 2017, 13 (3):e1006682 PLoS Genet.en
dc.identifier.issn1553-7404-
dc.identifier.pmid28346462-
dc.identifier.doi10.1371/journal.pgen.1006682-
dc.identifier.urihttp://hdl.handle.net/10033/621221-
dc.description.abstractUnderstanding 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.en
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshAnimalsen
dc.subject.meshBase Sequenceen
dc.subject.meshBlotting, Westernen
dc.subject.meshCell Cycleen
dc.subject.meshCell Proliferationen
dc.subject.meshCells, Cultureden
dc.subject.meshCyclin-Dependent Kinase Inhibitor p15en
dc.subject.meshCyclin-Dependent Kinase Inhibitor p16en
dc.subject.meshGene Expression Regulationen
dc.subject.meshGene Knockdown Techniquesen
dc.subject.meshHEK293 Cellsen
dc.subject.meshHepatocyte Nuclear Factor 1-alphaen
dc.subject.meshHumansen
dc.subject.meshMiceen
dc.subject.meshMice, Transgenicen
dc.subject.meshMouse Embryonic Stem Cellsen
dc.subject.meshPromoter Regions, Geneticen
dc.subject.meshReverse Transcriptase Polymerase Chain Reactionen
dc.subject.meshWnt Signaling Pathwayen
dc.titleWnt/Tcf1 pathway restricts embryonic stem cell cycle through activation of the Ink4/Arf locus.en
dc.typeArticleen
dc.contributor.departmentTwinCore, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.en
dc.identifier.journalPLoS geneticsen

Related articles on PubMed

This item is licensed under a Creative Commons License
Creative Commons
All Items in HZI are protected by copyright, with all rights reserved, unless otherwise indicated.