Activin/Nodal signalling maintains pluripotency by controlling Nanog expression
Activin/Nodal signalling maintains pluripotency by controlling Nanog expression
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DOI：
10.1242/dev.033951
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发表时间：
2009-04-15
期刊：
影响因子：
4.6
通讯作者：
Pedersen, Roger A.
中科院分区：
文献类型：
--
作者：
Vallier, Ludovic;Mendjan, Sasha;Pedersen, Roger A.
胚胎干细胞（ESC）的多能性状态赋予它们分化成三个初级胚层（外胚层、中胚层和内胚层）的能力，成体的所有细胞都源自所述初级胚层。因此，了解控制多能性的机制对于驱动人多能细胞分化成可用于临床应用的细胞类型是必不可少的。激活素/Nodal信号通路对于维持人ESC和小鼠外胚层干细胞（EpiSC）中的多能性是必需的，但其实现这种作用的分子机制仍然不清楚。在这里，我们证明了激活素/Nodal信号传导控制人ESC和小鼠EpiSC中关键多能性因子Nanog的表达。Nanog进而阻止FGF信号传导诱导的神经外胚层分化，并限制Smad 2/3级联的转录活性，阻断沿着内胚层谱系的进展。这种负反馈回路在神经外胚层和中内胚层分化中施加停滞，从而维持人ESC和小鼠EpiSC的多能状态。
The pluripotent status of embryonic stem cells (ESCs) confers upon them the capacity to differentiate into the three primary germ layers, ectoderm, mesoderm and endoderm, from which all the cells of the adult body are derived. An understanding of the mechanisms controlling pluripotency is thus essential for driving the differentiation of human pluripotent cells into cell types useful for clinical applications. The Activin/Nodal signalling pathway is necessary to maintain pluripotency in human ESCs and in mouse epiblast stem cells (EpiSCs), but the molecular mechanisms by which it achieves this effect remain obscure. Here, we demonstrate that Activin/Nodal signalling controls expression of the key pluripotency factor Nanog in human ESCs and in mouse EpiSCs. Nanog in turn prevents neuroectoderm differentiation induced by FGF signalling and limits the transcriptional activity of the Smad2/3 cascade, blocking progression along the endoderm lineage. This negative-feedback loop imposes stasis in neuroectoderm and mesendoderm differentiation, thereby maintaining the pluripotent status of human ESCs and mouse EpiSCs.