P120-catenin regulates REST/CoREST, and modulates mouse embryonic stem cell differentiation

Abstract

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