SHP-1 arrests mouse early embryo development through downregulation of Nanog by dephosphorylation of STAT3

PLoS One. 2014 Jan 21;9(1):e86330. doi: 10.1371/journal.pone.0086330. eCollection 2014.

Abstract

Src-homology protein tyrosine phosphatase-1 (SHP-1) is a protein tyrosine phosphatase that is implicated in the regulation of growth, differentiation, survival, apoptosis and proliferation of hematopoietic cells and other cell types. Here, we found that SHP-1 is involved in regulation of early embryonic development. Embryos overexpressing SHP-1 were mainly arrested at the 8-cell stage, and Nanog mRNA expression was first observed in the morulae that showed down-regulation of SHP-1. These results suggested an antagonistic relationship between SHP-1 and Nanog during early embryonic development. Next, the specific mechanism was examined in mouse F9 embryonal carcinoma cells. We confirmed that signal transducer and activator of transcription 3 (STAT3) was a substrate for SHP-1 by co-immunoprecipitation. Using overexpression and knockdown strategies, we found that SHP-1 participated in regulation of Nanog expression. Furthermore, site mutation of STAT3 was performed to confirm that SHP-1 was responsible for rapid STAT3 dephosphorylation and a decrease of Nanog expression in F9 cells. These findings suggest that SHP-1 plays a crucial role during early embryonic development. Thus, SHP-1 may function as a key regulator for Nanog that specifically demarcates the nascent epiblast, coincident with the domain of X chromosome reprogramming.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Down-Regulation / genetics*
  • Embryonal Carcinoma Stem Cells
  • Embryonic Development / genetics*
  • Homeodomain Proteins / genetics*
  • Immunoprecipitation / methods
  • Mice
  • Nanog Homeobox Protein
  • Phosphorylation / genetics*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics*
  • STAT3 Transcription Factor / genetics*
  • Signal Transduction / genetics

Substances

  • Homeodomain Proteins
  • Nanog Homeobox Protein
  • Nanog protein, mouse
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Ptpn6 protein, mouse

Grants and funding

This work was supported by the National High Technology Research and Development Program of China (863 Program) (No. 2011AA100303) (http://www.most.gov.cn). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.