Hamilton William B, Brickman Joshua M
The Danish Stem Cell Centre (DanStem), University of Copenhagen, 3B Blegdamsvej, 2200 Copenhagen, Denmark.
The Danish Stem Cell Centre (DanStem), University of Copenhagen, 3B Blegdamsvej, 2200 Copenhagen, Denmark.
Cell Rep. 2014 Dec 24;9(6):2056-70. doi: 10.1016/j.celrep.2014.11.032. Epub 2014 Dec 18.
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.
通过Erk激活的Fgf信号传导与神经诱导以及胚胎干细胞（ESC）向所有体细胞谱系分化的起始状态的产生有关。为了剖析Erk在ESC自我更新和谱系特化中的作用，我们在各种体外分化环境中探索了该信号通路的需求。Erk信号传导的药理学抑制和功能丧失性基因分析相结合，揭示了Erk信号传导在内胚层分化而非神经分化中的作用。尽管Erk磷酸化完全受阻，神经分化仍正常发生。支持这一点的是，ESC中的Erk激活通过抑制多能/外胚层网络，解除了原始内胚层（PrE）基因表达的抑制。对Erk激活的早期反应与功能性PrE起始相关，而持续的Erk活性则导致PrE分化。综上所述，我们的结果表明，Erk信号传导抑制多能基因表达以实现内胚层分化。
