An FGF4-FRS2alpha-Cdx2 axis in trophoblast stem cells induces Bmp4 to regulate proper growth of early mouse embryos

Stem Cells. 2010 Jan;28(1):113-21. doi: 10.1002/stem.247.


A variety of stem cells are controlled by the actions of multiple growth factors in vitro. However, it remains largely unclear how growth factors control the proliferation and differentiation of stem cells in vivo. Here, we describe a novel paracrine mechanism for regulating a stem cell niche in early mammalian embryos, which involves communication between the inner cell mass (ICM) and the trophectoderm, from which embryonic stem (ES) cells and trophoblast stem (TS) cells can be derived, respectively. It is known that ES cells produce fibroblast growth factor (FGF)4 and that TS cells produce bone morphogenetic protein (Bmp)4. We provide evidence that FRS2alpha mediates activation of the extracellular signal-regulated progein kinase (ERK) pathway to enhance expression of transcription factor Cdx2 in TS cells in response to FGF4. Cdx2 in turn binds to an FGF4-responsive enhancer element of the promoter region of Bmp4, leading to production and secretion of Bmp4. Moreover, exogenous Bmp4 is able to rescue the defective growth of Frs2alpha-null ICM. These findings suggest an important role of Cdx2 for production of Bmp4 in TS cells to promote the proper growth of early mouse embryos.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Flanking Region
  • Animals
  • Binding Sites
  • Blastocyst Inner Cell Mass / cytology
  • Blastocyst Inner Cell Mass / drug effects
  • Blastocyst Inner Cell Mass / metabolism*
  • Bone Morphogenetic Protein 4 / genetics
  • Bone Morphogenetic Protein 4 / metabolism*
  • CDX2 Transcription Factor
  • Carrier Proteins / metabolism
  • Cell Differentiation* / drug effects
  • Cell Differentiation* / genetics
  • Cell Proliferation* / drug effects
  • Cells, Cultured
  • Embryonic Stem Cells / drug effects
  • Embryonic Stem Cells / metabolism*
  • Enhancer Elements, Genetic
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fibroblast Growth Factor 4 / metabolism*
  • Gene Expression Regulation, Developmental
  • Homeodomain Proteins / metabolism*
  • Introns
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Paracrine Communication
  • Protein Kinase Inhibitors / pharmacology
  • RNA Interference
  • RNA, Messenger / metabolism
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Time Factors
  • Transcription Factors / metabolism*
  • Transfection
  • Trophoblasts / drug effects
  • Trophoblasts / metabolism*


  • Bmp4 protein, mouse
  • Bone Morphogenetic Protein 4
  • CDX2 Transcription Factor
  • Carrier Proteins
  • Cdx2 protein, mouse
  • FRS2alpha protein, mouse
  • Fgf4 protein, mouse
  • Fibroblast Growth Factor 4
  • Homeodomain Proteins
  • Membrane Proteins
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • Recombinant Proteins
  • Transcription Factors
  • noggin protein
  • Extracellular Signal-Regulated MAP Kinases