An FGF4-FRS2α-Cdx2 axis in trophoblast stem cells induces Bmp4 to regulate proper growth of early mouse embryos

Michiko Murohashi, Takahisa Nakamura, Satoshi Tanaka, Taeko Ichise, Nobuaki Yoshida, Tadashi Yamamoto, Masabumi Shibuya, Joseph Schlessinger, Noriko Gotoh

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)


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 FRS2α 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 Frs2α-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.

Original languageEnglish
Pages (from-to)113-121
Number of pages9
JournalStem Cells
Issue number1
Publication statusPublished - 2010 Jan
Externally publishedYes


  • Bmp4
  • Cdx2
  • FRS2α
  • Stem cell niche
  • Trophectoderm
  • Trophoblast stem cells

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology


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