Tissue-Specific Stem Cells

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An FGF4-FRS2α-Cdx2 Axis in Trophoblast Stem Cells Induces Bmp4 to Regulate Proper Growth of Early Mouse Embryos†‡§

  1. Michiko Murohashi1,2,
  2. Takahisa Nakamura3,
  3. Satoshi Tanaka5,
  4. Taeko Ichise4,
  5. Nobuaki Yoshida4,
  6. Tadashi Yamamoto3,
  7. Masabumi Shibuya1,
  8. Joseph Schlessinger6,
  9. Noriko Gotoh1,2,¶,*

Article first published online: 3 NOV 2009

DOI: 10.1002/stem.247

Issue

STEM CELLS

STEM CELLS

Volume 28, Issue 1, pages 113–121, January 2010

Additional Information

How to Cite

Murohashi, M., Nakamura, T., Tanaka, S., Ichise, T., Yoshida, N., Yamamoto, T., Shibuya, M., Schlessinger, J. and Gotoh, N. (2010), An FGF4-FRS2α-Cdx2 Axis in Trophoblast Stem Cells Induces Bmp4 to Regulate Proper Growth of Early Mouse Embryos. STEM CELLS, 28: 113–121. doi: 10.1002/stem.247

Author Information

  1. 1

    Division of Genetics, University of Tokyo, Tokyo, Japan

  2. 2

    Division of Systems Biomedical Technology, University of Tokyo, Tokyo, Japan

  3. 3

    Division of Oncology, University of Tokyo, Tokyo, Japan

  4. 4

    Gene Expression and Regulation, Institute of Medical Science, University of Tokyo, Tokyo, Japan

  5. 5

    Laboratory of Cellular Biochemistry, Animal Resource Science/Veterinary Medical Science, University of Tokyo, Tokyo, Japan

  6. 6

    Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA

  1. Telephone: +81-3-5449-5629; Fax: +81-3-5449-5425

*Division of Systems Biomedical Technology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan

  1. †

    Author contributions: M.M.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing; T.N., S.T., and T.I.: provision of study material; N.Y. and T.Y.: administrative support; M.S.: administrative support, financial support; J.S.: provision of study material or patients, final approval of manuscript; N.G.: conception and design, manuscript writing, final approval of manuscript, financial support.

  2. ‡

    Disclosure of potential conflicts of interest is found at the end of this article.

  3. §

    First published online in STEM CELLS EXPRESS November 3, 2009.

Publication History

  1. Issue published online: 12 JAN 2010
  2. Article first published online: 3 NOV 2009
  3. Accepted manuscript online: 3 NOV 2009 12:00AM EST
  4. Manuscript Accepted: 24 OCT 2009
  5. Manuscript Received: 14 MAY 2009

Funded by

  • Grants-in-Aid for Special Project Research on Stem Cells. Grant Numbers: 17013025, 17045008
  • Cancer-Bioscience. Grant Number: 17014020
  • Ministry of Education, Science, Sports and Culture of Japan
  • NOVARTIS Foundation (Japan) for the Promotion of Science
  • NIH grants. Grant Numbers: AR 051448, AR 051886

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Keywords:

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

Abstract

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. STEM CELLS 2010;28:113–121

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