Esrrb Is a Pivotal Target of the Gsk3/Tcf3 Axis Regulating Embryonic Stem Cell Self-Renewal

• DOI: 10.1016/j.stem.2012.06.008
• Publication Date: 2012-10-04T15:31:06Z
• Authors: Graziano Martello; Toshimi Sugimoto; Evangelia Diamanti; Anagha Joshi; Rebecca Hannah; Satoshi Ohtsuka; Berthold Göttgens; Hitoshi Niwa; Austin Smith
• Keywords: Pluripotent Stem Cells; 0301 basic medicine; Genome; Cell Survival; Gene Expression Regulation, Developmental; Cell Differentiation; Cell Biology; Leukemia Inhibitory Factor; Article; Cell Line; Glycogen Synthase Kinase 3; Mice; 03 medical and health sciences; Receptors, Estrogen; Genetics; Basic Helix-Loop-Helix Transcription Factors; Molecular Medicine; Animals; Erratum; RNA, Small Interfering; Embryonic Stem Cells

Inhibition of glycogen synthase kinase-3 (Gsk3) supports mouse embryonic stem cells (ESCs) by modulating Tcf3, but the critical targets downstream Tcf3 are unclear. We analyzed intersection between genome localization and transcriptome data sets to identify genes repressed Tcf3. Among these, manipulations Esrrb gave distinctive phenotypes in functional assays. Knockdown knockout eliminated response Gsk3 inhibition, causing extinction pluripotency markers loss colony forming capability. Conversely, forced expression phenocopied inhibition or deletion suppressing differentiation sustaining self-renewal. Thus nuclear receptor is necessary sufficient mediate self-renewal inhibition. Leukaemia inhibitory factor (LIF) regulates ESCs through Stat3, independently Consistent with parallel operation, LIF accommodated remained pluripotent. These findings highlight a key role for regulating naive pluripotent state illustrate compensation among core factors.