title: BRACHYURY and CDX2 mediate BMP-induced differentiation of human and mouse pluripotent stem cells into embryonic and extraembryonic lineages.
abstract: BMP is thought to induce hESC differentiation toward multiple lineages including mesoderm and trophoblast. The BMP-induced trophoblast phenotype is a long-standing paradox in stem cell biology. Here we readdressed BMP function in hESCs and mouse epiblast-derived cells. We found that BMP4 cooperates with FGF2 (via ERK) to induce mesoderm and to inhibit endoderm differentiation. These conditions induced cells with high levels of BRACHYURY (BRA) that coexpressed CDX2. BRA was necessary for and preceded CDX2 expression; both genes were essential for expression not only of mesodermal genes but also of trophoblast-associated genes. Maximal expression of the latter was seen in the absence of FGF but these cells coexpressed mesodermal genes and moreover they differed in cell surface and epigenetic properties from placental trophoblast. We conclude that BMP induces human and mouse pluripotent stem cells primarily to form mesoderm, rather than trophoblast, acting through BRA and CDX2.
authors.affiliation: The Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, Cambridge CB2 0SZ, UK. asb63@cam.ac.uk
authors.forename: Andreia S
authors.initials: AS
authors.lastname: Bernardo
authors.forename: Tiago
authors.initials: T
authors.lastname: Faial
authors.forename: Lucy
authors.initials: L
authors.lastname: Gardner
authors.forename: Kathy K
authors.initials: KK
authors.lastname: Niakan
authors.forename: Daniel
authors.initials: D
authors.lastname: Ortmann
authors.forename: Claire E
authors.initials: CE
authors.lastname: Senner
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Callery
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Trotter
authors.forename: Myriam
authors.initials: M
authors.lastname: Hemberger
authors.forename: James C
authors.initials: JC
authors.lastname: Smith
authors.forename: Lee
authors.initials: L
authors.lastname: Bardwell
authors.forename: Ashley
authors.initials: A
authors.lastname: Moffett
authors.forename: Roger A
authors.initials: RA
authors.lastname: Pedersen
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology*; D000071616:CDX2 Transcription Factor; D002454:Cell Differentiation / Q000187:drug effects*; D019070:Cell Lineage / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005326:Fetal Proteins / Q000235:genetics / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000235:genetics; D015292:Glycoprotein Hormones, alpha Subunit / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053552:Keratin-7 / Q000235:genetics / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000098908:Brachyury Protein
chemical_list: D055415:Bone Morphogenetic Protein 4; D000071616:CDX2 Transcription Factor; D002867:Chromones; D005326:Fetal Proteins; D016222:Fibroblast Growth Factor 2; D015292:Glycoprotein Hormones, alpha Subunit; D018398:Homeodomain Proteins; D053552:Keratin-7; D009025:Morpholines; D009479:Neuropeptides; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D000098908:Brachyury Protein; C491270:CDX2 protein, human; C554042:CGA protein, human; C487514:Cdx2 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one