Regulation of extra-embryonic endoderm stem cell differentiation by Nodal and Cripto signaling

Development. 2011 Sep;138(18):3885-95. doi: 10.1242/dev.065656.


The signaling pathway for Nodal, a ligand of the TGFβ superfamily, plays a central role in regulating the differentiation and/or maintenance of stem cell types that can be derived from the peri-implantation mouse embryo. Extra-embryonic endoderm stem (XEN) cells resemble the primitive endoderm of the blastocyst, which normally gives rise to the parietal and the visceral endoderm in vivo, but XEN cells do not contribute efficiently to the visceral endoderm in chimeric embryos. We have found that XEN cells treated with Nodal or Cripto (Tdgf1), an EGF-CFC co-receptor for Nodal, display upregulation of markers for visceral endoderm as well as anterior visceral endoderm (AVE), and can contribute to visceral endoderm and AVE in chimeric embryos. In culture, XEN cells do not express Cripto, but do express the related EGF-CFC co-receptor Cryptic (Cfc1), and require Cryptic for Nodal signaling. Notably, the response to Nodal is inhibited by the Alk4/Alk5/Alk7 inhibitor SB431542, but the response to Cripto is unaffected, suggesting that the activity of Cripto is at least partially independent of type I receptor kinase activity. Gene set enrichment analysis of genome-wide expression signatures generated from XEN cells under these treatment conditions confirmed the differing responses of Nodal- and Cripto-treated XEN cells to SB431542. Our findings define distinct pathways for Nodal and Cripto in the differentiation of visceral endoderm and AVE from XEN cells and provide new insights into the specification of these cell types in vivo.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics*
  • Cell Line
  • Embryo, Mammalian
  • Embryonic Stem Cells / drug effects
  • Embryonic Stem Cells / metabolism
  • Embryonic Stem Cells / physiology*
  • Endoderm / cytology*
  • Endoderm / drug effects
  • Endoderm / metabolism
  • Endoderm / physiology*
  • Epidermal Growth Factor / genetics
  • Epidermal Growth Factor / metabolism
  • Epidermal Growth Factor / pharmacology
  • Epidermal Growth Factor / physiology*
  • Extraembryonic Membranes / cytology
  • Extraembryonic Membranes / physiology
  • Female
  • Gene Expression Profiling
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Membrane Glycoproteins / pharmacology
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred ICR
  • Mice, Transgenic
  • Microarray Analysis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Neoplasm Proteins / pharmacology
  • Neoplasm Proteins / physiology*
  • Nodal Protein / genetics
  • Nodal Protein / metabolism
  • Nodal Protein / pharmacology
  • Nodal Protein / physiology*
  • Pregnancy
  • Signal Transduction / drug effects
  • Signal Transduction / genetics


  • Membrane Glycoproteins
  • Neoplasm Proteins
  • Nodal Protein
  • Nodal protein, mouse
  • Tdgf1 protein, mouse
  • Epidermal Growth Factor