title: β-catenin fluctuates in mouse ESCs and is essential for Nanog-mediated reprogramming of somatic cells to pluripotency.
abstract: The Wnt/β-catenin pathway and Nanog are key regulators of embryonic stem cell (ESC) pluripotency and the reprogramming of somatic cells. Here, we demonstrate that the repression of Dkk1 by Nanog, which leads indirectly to β-catenin activation, is essential for reprogramming after fusion of ESCs overexpressing Nanog. In addition, β-catenin is necessary in Nanog-dependent conversion of preinduced pluripotent stem cells (pre-iPSCs) into iPSCs. The activation of β-catenin by Nanog causes fluctuations of β-catenin in ESCs cultured in serum plus leukemia inhibitory factor (serum+LIF) medium, in which protein levels of key pluripotency factors are heterogeneous. In 2i+LIF medium, which favors propagation of ESCs in a ground state of pluripotency with many pluripotency genes losing mosaic expression, we show Nanog-independent β-catenin fluctuations. Overall, we demonstrate Nanog and β-catenin cooperation in establishing naive pluripotency during the reprogramming process and their correlated heterogeneity in ESCs primed toward differentiation.
authors.affiliation: Centre for Genomic Regulation (CRG), 08003 Barcelona, Spain; Department of Engineering Mathematics, University of Bristol, Bristol BS8 1UB, UK.
authors.forename: Lucia
authors.initials: L
authors.lastname: Marucci
authors.affiliation: Centre for Genomic Regulation (CRG), 08003 Barcelona, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Pedone
authors.affiliation: Centre for Genomic Regulation (CRG), 08003 Barcelona, Spain.
authors.forename: Umberto
authors.initials: U
authors.lastname: Di Vicino
authors.affiliation: Centre for Genomic Regulation (CRG), 08003 Barcelona, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: Sanuy-Escribano
authors.affiliation: Centre for Genomic Regulation (CRG), 08003 Barcelona, Spain.
authors.forename: Mark
authors.initials: M
authors.lastname: Isalan
authors.affiliation: Centre for Genomic Regulation (CRG), 08003 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain. Electronic address: pia.cosma@crg.es.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Cosma
mesh_terms: D000818:Animals; D065150:Cellular Reprogramming; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology; D051379:Mice; D000071317:Nanog Homeobox Protein; D039904:Pluripotent Stem Cells / Q000166:cytology; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C501127:Dkk1 protein, mouse; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D053605:Leukemia Inhibitory Factor; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D051176:beta Catenin