BRACHYURY and CDX2 mediate BMP-induced differentiation of human and mouse pluripotent stem cells into embryonic and extraembryonic lineages

Cell Stem Cell. 2011 Aug 5;9(2):144-55. doi: 10.1016/j.stem.2011.06.015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Protein 4 / pharmacology*
  • CDX2 Transcription Factor
  • Cell Differentiation / drug effects*
  • Cell Lineage / drug effects*
  • Chromones / pharmacology
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / drug effects
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / drug effects
  • Embryonic Stem Cells / metabolism
  • Fetal Proteins / genetics
  • Fetal Proteins / metabolism*
  • Fibroblast Growth Factor 2 / pharmacology
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Regulatory Networks / genetics
  • Glycoprotein Hormones, alpha Subunit / genetics
  • Glycoprotein Hormones, alpha Subunit / metabolism
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Keratin-7 / genetics
  • Keratin-7 / metabolism
  • Mesoderm / cytology
  • Mesoderm / drug effects
  • Mesoderm / metabolism
  • Mice
  • Morpholines / pharmacology
  • Neuropeptides / genetics
  • Neuropeptides / metabolism
  • Pluripotent Stem Cells / cytology*
  • Pluripotent Stem Cells / drug effects
  • Pluripotent Stem Cells / metabolism
  • Signal Transduction / drug effects
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Trophoblasts / cytology
  • Trophoblasts / drug effects
  • Trophoblasts / metabolism

Substances

  • Bone Morphogenetic Protein 4
  • CDX2 Transcription Factor
  • CDX2 protein, human
  • CGA protein, human
  • Cdx2 protein, mouse
  • Chromones
  • Fetal Proteins
  • Glycoprotein Hormones, alpha Subunit
  • Homeodomain Proteins
  • Keratin-7
  • Morpholines
  • Neuropeptides
  • T-Box Domain Proteins
  • Transcription Factors
  • Fibroblast Growth Factor 2
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Brachyury protein