title: Activin/Nodal signalling maintains pluripotency by controlling Nanog expression.
abstract: The pluripotent status of embryonic stem cells (ESCs) confers upon them the capacity to differentiate into the three primary germ layers, ectoderm, mesoderm and endoderm, from which all the cells of the adult body are derived. An understanding of the mechanisms controlling pluripotency is thus essential for driving the differentiation of human pluripotent cells into cell types useful for clinical applications. The Activin/Nodal signalling pathway is necessary to maintain pluripotency in human ESCs and in mouse epiblast stem cells (EpiSCs), but the molecular mechanisms by which it achieves this effect remain obscure. Here, we demonstrate that Activin/Nodal signalling controls expression of the key pluripotency factor Nanog in human ESCs and in mouse EpiSCs. Nanog in turn prevents neuroectoderm differentiation induced by FGF signalling and limits the transcriptional activity of the Smad2/3 cascade, blocking progression along the endoderm lineage. This negative-feedback loop imposes stasis in neuroectoderm and mesendoderm differentiation, thereby maintaining the pluripotent status of human ESCs and mouse EpiSCs.
authors.affiliation: Department of Surgery and Laboratory For Regenerative Medicine, West Forvie Building, Robinson Way, University of Cambridge, Cambridge CB2 0SZ, UK. lv225@cam.ac.uk
authors.forename: Ludovic
authors.initials: L
authors.lastname: Vallier
authors.forename: Sasha
authors.initials: S
authors.lastname: Mendjan
authors.forename: Stephanie
authors.initials: S
authors.lastname: Brown
authors.forename: Zhenzhi
authors.initials: Z
authors.lastname: Chng
authors.forename: Adrian
authors.initials: A
authors.lastname: Teo
authors.forename: Lucy E
authors.initials: LE
authors.lastname: Smithers
authors.forename: Matthew W B
authors.initials: MW
authors.lastname: Trotter
authors.forename: Candy H-H
authors.initials: CH
authors.lastname: Cho
authors.forename: Amelie
authors.initials: A
authors.lastname: Martinez
authors.forename: Peter
authors.initials: P
authors.lastname: Rugg-Gunn
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Brons
authors.forename: Roger A
authors.initials: RA
authors.lastname: Pedersen
mesh_terms: D028341:Activins / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D005855:Germ Layers / Q000196:embryology / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D000071317:Nanog Homeobox Protein; D009474:Neurons / Q000378:metabolism; D055457:Nodal Protein / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism
chemical_list: D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D055457:Nodal Protein; D051899:Smad2 Protein; D051900:Smad3 Protein; D016222:Fibroblast Growth Factor 2; D028341:Activins