Nodal protein processing and fibroblast growth factor 4 synergize to maintain a trophoblast stem cell microenvironment

Proc Natl Acad Sci U S A. 2004 Nov 2;101(44):15656-60. doi: 10.1073/pnas.0405429101. Epub 2004 Oct 25.

Abstract

Before implantation in the uterus, mammalian embryos set aside trophoblast stem cells that are maintained in the extraembryonic ectoderm (ExE) during gastrulation to generate the fetal portion of the placenta. Their proliferation depends on diffusible signals from neighboring cells in the epiblast, including fibroblast growth factor 4 (Fgf4). Here, we show that Fgf4 expression is induced by the transforming growth factor beta-related protein Nodal. Together with Fgf4, Nodal also acts directly on neighboring ExE to sustain a microenvironment that inhibits precocious differentiation of trophoblast stem cells. Because the ExE itself produces the proteases Furin and PACE4 to activate Nodal, it represents the first example, to our knowledge, of a stem cell compartment that actively maintains its own microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Female
  • Fibroblast Growth Factor 4
  • Fibroblast Growth Factors / genetics*
  • Furin / deficiency
  • Furin / genetics
  • Furin / metabolism
  • Gene Expression / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • Nodal Protein
  • Pregnancy
  • Proprotein Convertases
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins / genetics*
  • Recombinant Proteins / pharmacology
  • Serine Endopeptidases / deficiency
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism
  • Stem Cells / cytology*
  • Stem Cells / metabolism*
  • Tissue Culture Techniques
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta / pharmacology
  • Trophoblasts / cytology*
  • Trophoblasts / metabolism*

Substances

  • Fgf4 protein, mouse
  • Fibroblast Growth Factor 4
  • Nodal Protein
  • Nodal protein, mouse
  • Proto-Oncogene Proteins
  • Recombinant Proteins
  • Transforming Growth Factor beta
  • Fibroblast Growth Factors
  • Pcsk6 protein, mouse
  • Proprotein Convertases
  • Serine Endopeptidases
  • Furin