Erk Signaling Suppresses Embryonic Stem Cell Self-Renewal to Specify Endoderm
Erk Signaling Suppresses Embryonic Stem Cell Self-Renewal to Specify Endoderm
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DOI：
10.1016/j.celrep.2014.11.032
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发表时间：
2014-12-24
期刊：
影响因子：
8.8
通讯作者：
Brickman, Joshua M.
中科院分区：
文献类型：
--
作者：
Hamilton, William B.;Brickman, Joshua M.
通过Erk激活的FGF信号传导与神经诱导和用于胚胎干细胞（ESC）分化为所有体细胞谱系的致敏状态的产生相关联。为了剖析Erk在ESC自我更新和谱系特化中的作用，我们探讨了在各种体外分化环境中对该途径的要求。Erk信号传导的药理学抑制和遗传功能丧失的组合揭示了Erk信号传导在内胚层而非神经分化中的作用。尽管Erk磷酸化被完全阻断，神经分化仍正常发生。为了支持这一点，ESCs中的Erk激活通过抑制多能/上胚层网络而解除了原始内胚层（PrE）基因表达的抑制。Erk激活的早期反应与功能性PrE启动相关，而持续的Erk活性导致PrE分化。总之，我们的研究结果表明，Erk信号抑制多能基因表达，使内胚层分化。
Fgf signaling via Erk activation has been associated with both neural induction and the generation of a primed state for the differentiation of embryonic stem cells (ESCs) to all somatic lineages. To dissect the role of Erk in both ESC self-renewal and lineage specification, we explored the requirements for this pathway in various in vitro differentiation settings. A combination of pharmacological inhibition of Erk signaling and genetic loss of function reveal a role for Erk signaling in endodermal, but not neural differentiation. Neural differentiation occurs normally despite a complete block to Erk phosphorylation. In support of this, Erk activation in ESCs derepresses primitive endoderm (PrE) gene expression as a consequence of inhibiting the pluripotent/epiblast network. The early response to Erk activation correlates with functional PrE priming, whereas sustained Erk activity results in PrE differentiation. Taken together, our results suggest that Erk signaling suppresses pluripotent gene expression to enable endodermal differentiation.