The roles of FGF and MAP kinase signaling in the segregation of the epiblast and hypoblast cell lineages in bovine and human embryos
The roles of FGF and MAP kinase signaling in the segregation of the epiblast and hypoblast cell lineages in bovine and human embryos
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DOI：
10.1242/dev.071688
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发表时间：
2012-03-01
期刊：
影响因子：
4.6
通讯作者：
Roelen, Bernard A. J.
中科院分区：
文献类型：
--
作者：
Kuijk, Ewart W.;van Tol, Leni T. A.;Roelen, Bernard A. J.
在哺乳动物着床前发育的囊胚阶段，形成了三种不同的细胞系：滋养外胚层、下胚层（原始内胚层）和外胚层。在多种物种中无法衍生出胚胎干（ES）细胞系表明，在早期谱系规范中涉及的细胞信号通路中，物种之间存在分歧。在小鼠中，原始内胚层谱系与多能外胚层谱系的分离依赖于FGF/MAP激酶信号传导，但尚不清楚这在物种之间是否保守。在这里，我们通过调节培养胚胎中的FGF/MAP激酶信号通路，研究了牛和人胚胎中下胚层和外胚层谱系的分离。用FGF4和肝素刺激的牛胚胎形成完全由下胚层细胞组成的内细胞团（ICMs），没有外胚层细胞。在牛胚胎中抑制MEK导致ICMs外胚层前体增加，下胚层前体减少。MEK抑制后，下母细胞前体细胞未完全消融，表明下母细胞分化有其他因素参与。令人惊讶的是，抑制MEK上游的FGF信号传导对牛发育过程中外胚层和下胚层前体细胞数量没有影响，这表明GATA6的表达并不依赖于FGF信号传导。相比之下，在人类胚胎中，尽管MEK抑制剂能够有效抑制人类胚胎干细胞中的ERK磷酸化，但抑制MEK并没有显著改变外胚层或下胚层前体细胞的数量。这些发现表明，在哺乳动物早期发育过程中，FGF/MAP激酶信号通路在控制下胚层细胞和外胚层细胞谱系选择中的作用存在内在差异。
At the blastocyst stage of mammalian pre-implantation development, three distinct cell lineages have formed: trophectoderm, hypoblast (primitive endoderm) and epiblast. The inability to derive embryonic stem (ES) cell lines in a variety of species suggests divergence between species in the cell signaling pathways involved in early lineage specification. In mouse, segregation of the primitive endoderm lineage from the pluripotent epiblast lineage depends on FGF/MAP kinase signaling, but it is unknown whether this is conserved between species. Here we examined segregation of the hypoblast and epiblast lineages in bovine and human embryos through modulation of FGF/MAP kinase signaling pathways in cultured embryos. Bovine embryos stimulated with FGF4 and heparin form inner cell masses (ICMs) composed entirely of hypoblast cells and no epiblast cells. Inhibition of MEK in bovine embryos results in ICMs with increased epiblast precursors and decreased hypoblast precursors. The hypoblast precursor population was not fully ablated upon MEK inhibition, indicating that other factors are involved in hypoblast differentiation. Surprisingly, inhibition of FGF signaling upstream of MEK had no effects on epiblast and hypoblast precursor numbers in bovine development, suggesting that GATA6 expression is not dependent on FGF signaling. By contrast, in human embryos, inhibition of MEK did not significantly alter epiblast or hypoblast precursor numbers despite the ability of the MEK inhibitor to potently inhibit ERK phosphorylation in human ES cells. These findings demonstrate intrinsic differences in early mammalian development in the role of the FGF/MAP kinase signaling pathways in governing hypoblast versus epiblast lineage choices.