β-catenin coordinates with Jup and the TCF1/GATA6 axis to regulate human embryonic stem cell fate

Dev Biol. 2017 Nov 15;431(2):272-281. doi: 10.1016/j.ydbio.2017.09.004. Epub 2017 Sep 21.

Abstract

β-catenin-mediated signaling has been extensively studied in regard to its role in the regulation of human embryonic stem cells (hESCs). However, the results are controversial and the mechanism by which β-catenin regulates the hESC fate remains unclear. Here, we report that β-catenin and γ-catenin are functionally redundant in mediating hESC adhesion and are required for embryoid body formation, but both genes are dispensable for hESC maintenance, as the undifferentiated state of β-catenin and γ-catenin double deficient hESCs can be maintained. Overexpression of β-catenin induces rapid hESC differentiation. Functional assays revealed that TCF1 plays a crucial role in hESC differentiation mediated by β-catenin. Forced expression of TCF1, but not other LEF1/TCF family members, resulted in hESC differentiation towards the definitive endoderm. Conversely, knockdown of TCF1 or inhibition of the interaction between TCF1 and β-catenin delayed hESC exit from pluripotency. Furthermore, we demonstrated that GATA6 plays a predominant role in TCF1-mediated hESC differentiation. Knockdown of GATA6 completely eliminated the effect of TCF1, while forced expression of GATA6 induced hESC differentiation. Our data thus reveal more detailed mechanisms for β-catenin in regulating hESC fate decisions and will expand our understanding of the self-renewal and differentiation circuitry in hESCs.

Keywords: Embryonic stem cells; GATA6; JUP; TCF1; β-catenin.

MeSH terms

  • Cell Adhesion
  • Cell Differentiation
  • Cell Lineage*
  • Cell Self Renewal
  • Desmoplakins / metabolism
  • Endoderm / cytology
  • GATA6 Transcription Factor / metabolism*
  • Human Embryonic Stem Cells / cytology*
  • Human Embryonic Stem Cells / metabolism*
  • Humans
  • Lymphoid Enhancer-Binding Factor 1 / metabolism*
  • Signal Transduction*
  • Transcription, Genetic
  • Up-Regulation
  • beta Catenin / metabolism*
  • gamma Catenin

Substances

  • Desmoplakins
  • GATA6 Transcription Factor
  • JUP protein, human
  • LEF1 protein, human
  • Lymphoid Enhancer-Binding Factor 1
  • beta Catenin
  • gamma Catenin