Primitive endoderm differentiates via a three-step mechanism involving Nanog and RTK signaling

Dev Cell. 2011 Dec 13;21(6):1005-13. doi: 10.1016/j.devcel.2011.10.019.

Abstract

During preimplantation mouse development, the inner cell mass (ICM) differentiates into two cell lineages--the epiblast and the primitive endoderm (PrE)--whose precursors are identifiable by reciprocal expression of Nanog and Gata6, respectively. PrE formation depends on Nanog by a non-cell-autonomous mechanism. To decipher early cell- and non-cell-autonomous effects, we performed a mosaic knockdown of Nanog and found that this is sufficient to induce a PrE fate cell autonomously. Strikingly, in Nanog null embryos, Gata6 expression is maintained, showing that initiation of the PrE program is Nanog independent. Treatment of Nanog null embryos with pharmacological inhibitors revealed that RTK dependency of Gata6 expression is initially direct but later indirect via Nanog repression. Moreover, we found that subsequent expression of Sox17 and Gata4--later markers of the PrE--depends on the presence of Fgf4 produced by Nanog-expressing cells. Thus, our results reveal three distinct phases in the PrE differentiation program.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • DNA Primers / genetics
  • Embryonic Development / genetics
  • Embryonic Development / physiology
  • Endoderm / embryology*
  • Endoderm / metabolism*
  • Fibroblast Growth Factor 4 / genetics
  • Fibroblast Growth Factor 4 / metabolism
  • GATA4 Transcription Factor / genetics
  • GATA4 Transcription Factor / metabolism
  • GATA6 Transcription Factor / genetics
  • GATA6 Transcription Factor / metabolism
  • Gene Expression Regulation, Developmental
  • Gene Knockdown Techniques
  • HMGB Proteins / genetics
  • HMGB Proteins / metabolism
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Nanog Homeobox Protein
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • SOXF Transcription Factors / genetics
  • SOXF Transcription Factors / metabolism
  • Signal Transduction

Substances

  • DNA Primers
  • Fgf4 protein, mouse
  • Fibroblast Growth Factor 4
  • GATA4 Transcription Factor
  • GATA6 Transcription Factor
  • Gata4 protein, mouse
  • Gata6 protein, mouse
  • HMGB Proteins
  • Homeodomain Proteins
  • Nanog Homeobox Protein
  • Nanog protein, mouse
  • RNA, Messenger
  • SOXF Transcription Factors
  • Sox17 protein, mouse
  • Receptor Protein-Tyrosine Kinases

Associated data

  • GEO/GSE27314