Esrrb Is a Pivotal Target of the Gsk3/Tcf3 Axis Regulating Embryonic Stem Cell Self-Renewal
Esrrb Is a Pivotal Target of the Gsk3/Tcf3 Axis Regulating Embryonic Stem Cell Self-Renewal
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DOI：
10.1016/j.stem.2013.04.020
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发表时间：
2013-05-02
期刊：
影响因子：
23.9
通讯作者：
Smith, Austin
中科院分区：
文献类型：
--
作者：
Martello, Graziano;Sugimoto, Toshimi;Diamanti, Evangelia;Joshi, Anagha;Hannah, Rebecca;Ohtsuka, Satoshi;Goettgens, Berthold;Niwa, Hitoshi;Smith, Austin
糖原合成酶激酶 3 (Gsk3) 的抑制通过调节 Tcf3 支持小鼠胚胎干细胞 (ESC)，但 Tcf3 下游的关键靶点尚不清楚。我们分析了基因组定位和转录组数据集之间的交叉点，以识别 Tcf3 抑制的基因。其中，Esrrb 的操作在功能测定中给出了独特的表型。敲低和基因敲除消除了对 Gsk3 抑制的反应，导致多能性标记消失和集落形成能力丧失。相反，强制表达通过抑制分化和维持自我更新来模仿 Gsk3 抑制或 Tcf3 缺失。因此，核受体 Esrrb 对于介导 Gsk3 抑制下游的自我更新是必要且充分的。白血病抑制因子 (LIF) 通过 Stat3 调节 ESC，独立于 Gsk3 抑制。与平行操作一致，LIF 中的 ESC 适应了 Esrrb 缺失并保持多能性。这些发现强调了 Esrrb 在调节初始多能状态中的关键作用，并说明了核心多能因子之间的补偿。
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.
影响因子：
23.9
作者：
Martello, Graziano;Sugimoto, Toshimi;Diamanti, Evangelia;Joshi, Anagha;Hannah, Rebecca;Ohtsuka, Satoshi;Goettgens, Berthold;Niwa, Hitoshi;Smith, Austin
通讯作者：
Smith, Austin