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

被引：316

作者：

Martello, Graziano ^{[1
,2
]}

Sugimoto, Toshimi ^{[5
,6
]}

Diamanti, Evangelia ^{[1
,3
,4
]}

Joshi, Anagha ^{[1
,3
,4
]}

Hannah, Rebecca ^{[1
,3
,4
]}

Ohtsuka, Satoshi ^{[5
]}

Goettgens, Berthold ^{[1
,3
,4
]}

Niwa, Hitoshi ^{[5
,6
]}

Smith, Austin ^{[1
,2
]}

机构：

[1] Univ Cambridge, Wellcome Trust Med Res Council Stem Cell Inst, Cambridge, England

[2] Univ Cambridge, Dept Biochem, Cambridge CB2 1QW, England

[3] Univ Cambridge, Cambridge Inst Med Res, Cambridge, England

[4] Univ Cambridge, Dept Haematol, Cambridge, England

[5] RIKEN Ctr Dev Biol, Kobe, Hyogo 6500047, Japan

[6] Kobe Univ, Grad Sch Med, Lab Dev & Regenerat Med, Chuo Ku, Kobe, Hyogo 6500017, Japan

来源：

CELL STEM CELL | 2012年 / 11卷 / 04期

基金：

英国生物技术与生命科学研究理事会; 英国医学研究理事会; 英国惠康基金;

关键词：

GROUND-STATE PLURIPOTENCY; MOUSE ES CELLS; BETA-CATENIN; PREVENT DIFFERENTIATION; TRANSCRIPTIONAL CONTROL; SIGNALING PATHWAYS; GENE-EXPRESSION; TCF3; WNT; NANOG;

D O I：

10.1016/j.stem.2012.06.008

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

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

引用

页码：491 / 504

页数：14

共 52 条

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