title: Distinct Signaling Requirements for the Establishment of ESC Pluripotency in Late-Stage EpiSCs.
abstract: It has previously been reported that mouse epiblast stem cell (EpiSC) lines comprise heterogeneous cell populations that are functionally equivalent to cells of either early- or late-stage postimplantation development. So far, the establishment of the embryonic stem cell (ESC) pluripotency gene regulatory network through the widely known chemical inhibition of MEK and GSK3beta has been impractical in late-stage EpiSCs. Here, we show that chemical inhibition of casein kinase 1alpha (CK1alpha) induces the conversion of recalcitrant late-stage EpiSCs into ESC pluripotency. CK1alpha inhibition directly results in the simultaneous activation of the WNT signaling pathway, together with inhibition of the TGFbeta/SMAD2 signaling pathway, mediating the rewiring of the gene regulatory network in favor of an ESC-like state. Our findings uncover a molecular mechanism that links CK1alpha to ESC pluripotency through the direct modulation of WNT and TGFbeta signaling.
authors.affiliation: Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany; Max Planck Institute for Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
authors.forename: Damir Jacob
authors.initials: DJ
authors.lastname: Illich
authors.affiliation: Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.
authors.forename: Miao
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Max Planck Institute for Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany; Technische Universität Dortmund, 44227 Dortmund, Germany.
authors.forename: Andrei
authors.initials: A
authors.lastname: Ursu
authors.affiliation: Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Osorno
authors.affiliation: Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.
authors.forename: Kee-Pyo
authors.initials: KP
authors.lastname: Kim
authors.affiliation: Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.
authors.forename: Juyong
authors.initials: J
authors.lastname: Yoon
authors.affiliation: Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany; IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain.
authors.forename: Marcos J
authors.initials: MJ
authors.lastname: Araúzo-Bravo
authors.affiliation: Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.
authors.forename: Guangming
authors.initials: G
authors.lastname: Wu
authors.affiliation: Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Esch
authors.affiliation: Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.
authors.forename: Davood
authors.initials: D
authors.lastname: Sabour
authors.affiliation: MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, Scotland.
authors.forename: Douglas
authors.initials: D
authors.lastname: Colby
authors.affiliation: University of Münster, 48149 Münster, Germany.
authors.forename: Kathrin S
authors.initials: KS
authors.lastname: Grassme
authors.affiliation: School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Chen
authors.affiliation: Human Stem Cell Pluripotency Laboratory, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany; Chemical Genomics Centre of the Max Planck Society, 44227 Dortmund, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Greber
authors.affiliation: Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Höing
authors.affiliation: Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany; University of Münster, 48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of Münster, 48149 Münster, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Herzog
authors.affiliation: Max Planck Institute for Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
authors.forename: Slava
authors.initials: S
authors.lastname: Ziegler
authors.affiliation: MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, Scotland.
authors.forename: Ian
authors.initials: I
authors.lastname: Chambers
authors.affiliation: School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Shaorong
authors.initials: S
authors.lastname: Gao
authors.affiliation: Max Planck Institute for Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany; Technische Universität Dortmund, 44227 Dortmund, Germany. Electronic address: herbert.waldmann@mpi-dortmund.mpg.de.
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
authors.affiliation: Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany; University of Münster, 48149 Münster, Germany. Electronic address: office@mpi-muenster.mpg.de.
authors.forename: Hans R
authors.initials: HR
authors.lastname: Schöler