title: β-catenin enhances Oct-4 activity and reinforces pluripotency through a TCF-independent mechanism.
abstract: Understanding the mechanisms regulating pluripotency in embryonic and induced pluripotent stem cells is required to ensure their safe use in clinical applications. Glycogen synthase kinase-3 (GSK-3) has emerged as an important regulator of pluripotency, based primarily on studies with small-molecule GSK-3 inhibitors. Here, we use mouse embryonic stem cells (ESCs) lacking GSK-3 to demonstrate that a single GSK-3 substrate, β-catenin, controls the ability of ESCs to exit the pluripotent state and to differentiate into neurectoderm. Unexpectedly, the effects of β-catenin on pluripotency do not appear to be dependent on TCF-mediated signaling, based on experiments utilizing a β-catenin C-terminal truncation mutant or highly efficient dominant-negative TCF strategies. Alternatively, we find that stabilized β-catenin forms a complex with and enhances the activity of Oct-4, a core component of the transcriptional network regulating pluripotency. Collectively, our data suggest previously underappreciated, divergent TCF-dependent and TCF-independent roles for β-catenin in ESCs.
authors.affiliation: Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Kelly
authors.forename: Deborah Y
authors.initials: DY
authors.lastname: Ng
authors.forename: Gowtham
authors.initials: G
authors.lastname: Jayakumaran
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Wood
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Koide
authors.forename: Bradley W
authors.initials: BW
authors.lastname: Doble
mesh_terms: D000818:Animals; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D047468:Immunoprecipitation; D051379:Mice; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D051822:T Cell Transcription Factor 1; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D050814:Octamer Transcription Factor-3; D051822:T Cell Transcription Factor 1; D051820:TCF Transcription Factors; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3