FGF signalling inhibits neural induction in human embryonic stem cells
FGF signalling inhibits neural induction in human embryonic stem cells
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DOI：
10.1038/emboj.2011.407
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发表时间：
2011-12-14
期刊：
影响因子：
11.4
通讯作者：
Schoeler, Hans R.
中科院分区：
文献类型：
--
作者：
Greber, Boris;Coulon, Philippe;Schoeler, Hans R.
人类胚胎干细胞(HESCs)可以在任何时间通过信号分子的作用退出自我更新计划，并沿着三个生殖层谱系分化。我们系统地研究了TGFb/Smad2、BMP/Smad1和Fgf/ERK三条信号通路在促进人胚胎干细胞向神经外胚层转化中的具体作用。在这方面，抑制Smad2和ERK信号有助于通过快速下调NANOG和OCT4来协同促进退出hESC的自我更新。相反，抑制Smad1信号通路可以维持SOX2的表达，并通过HAND1阻止非神经性分化。抑制成纤维细胞生长因子/ERK上调OTX2，继而诱导神经外胚层命运决定因素PAX6，揭示了FGF2在间接抑制hESCs中PAX6的新作用。因此，联合抑制这三条途径可在4d内形成高效的神经外胚层，随后，抑制成纤维细胞生长因子/ERK促进了向外周神经元的快速分化。我们的研究在hESCs的神经诱导中赋予了成纤维细胞生长因子/ERK信号的一个新的、双相的作用，这也可能在需要快速而有效地产生外周神经元的应用中具有实用价值。EMBO期刊(2011)30,4874-4884。DOI：10.1038/Intemj.2011.407；2011年11月15日在线发布
Human embryonic stem cells (hESCs) can exit the self-renewal programme, through the action of signalling molecules, at any given time and differentiate along the three germ layer lineages. We have systematically investigated the specific roles of three signalling pathways, TGFb/SMAD2, BMP/SMAD1, and FGF/ERK, in promoting the transition of hESCs into the neuroectoderm lineage. In this context, inhibition of SMAD2 and ERK signalling served to cooperatively promote exit from hESC self-renewal through the rapid downregulation of NANOG and OCT4. In contrast, inhibition of SMAD1 signalling acted to maintain SOX2 expression and prevent non-neural differentiation via HAND1. Inhibition of FGF/ERK upregulated OTX2 that subsequently induced the neuroectodermal fate determinant PAX6, revealing a novel role for FGF2 in indirectly repressing PAX6 in hESCs. Combined inhibition of the three pathways hence resulted in highly efficient neuroectoderm formation within 4 days, and subsequently, FGF/ERK inhibition promoted rapid differentiation into peripheral neurons. Our study assigns a novel, biphasic role to FGF/ERK signalling in the neural induction of hESCs, which may also have utility for applications requiring the rapid and efficient generation of peripheral neurons. The EMBO Journal (2011) 30, 4874-4884. doi: 10.1038/emboj.2011.407; Published online 15 November 2011