p120-catenin regulates REST and CoREST, and modulates mouse embryonic stem cell differentiation

J Cell Sci. 2014 Sep 15;127(Pt 18):4037-51. doi: 10.1242/jcs.151944. Epub 2014 Jul 29.

Abstract

Although the canonical Wnt pathway and β-catenin have been extensively studied, less is known about the role of p120-catenin (also known as δ1-catenin) in the nuclear compartment. Here, we report that p120-catenin binds and negatively regulates REST and CoREST (also known as Rcor1), a repressive transcriptional complex that has diverse developmental and pathological roles. Using mouse embryonic stem cells (mESCs), mammalian cell lines, Xenopus embryos and in vitro systems, we find that p120-catenin directly binds the REST-CoREST complex, displacing it from established gene targets to permit their transcriptional activation. Importantly, p120-catenin levels further modulate the mRNA and protein levels of Oct4 (also known as POU5F1), Nanog and Sox2, and have an impact upon the differentiation of mESCs towards neural fates. In assessing potential upstream inputs to this new p120-catenin-REST-CoREST pathway, REST gene targets were found to respond to the level of E-cadherin, with evidence suggesting that p120-catenin transduces signals between E-cadherin and the nucleus. In summary, we provide the first evidence for a direct upstream modulator and/or pathway regulating REST-CoREST, and reveal a substantial role for p120-catenin in the modulation of stem cell differentiation.

Keywords: CoREST; E-cadherin; Mouse embryonic stem cell; REST; p120-catenin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Catenins / genetics
  • Catenins / metabolism*
  • Cell Differentiation*
  • Co-Repressor Proteins
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / metabolism*
  • Humans
  • Mice
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Xenopus laevis

Substances

  • Catenins
  • Co-Repressor Proteins
  • Nerve Tissue Proteins
  • Octamer Transcription Factor-3
  • Pou5f1 protein, mouse
  • RE1-silencing transcription factor
  • Rcor2 protein, mouse
  • Repressor Proteins
  • delta catenin