Laboratory of Developmental Biology and Genetics (LDB&G), Department of Molecular Biology, Faculty of Science, University of South Bohemia, Branišovská 31, 37005 České Budějovice, Czech Republic.
Laboratory of Developmental Biology and Genetics (LDB&G), Department of Molecular Biology, Faculty of Science, University of South Bohemia, Branišovská 31, 37005 České Budějovice, Czech Republic Biology Centre of the Czech Academy of Sciences, Institute of Entomology, Branišovská 31, 37005 České Budějovice, Czech Republic
Open Biol. 2016 Sep;6(9). doi: 10.1098/rsob.160190.
During mouse preimplantation embryo development, the classically described second cell-fate decision involves the specification and segregation, in blastocyst inner cell mass (ICM), of primitive endoderm (PrE) from pluripotent epiblast (EPI). The active role of fibroblast growth factor (Fgf) signalling during PrE differentiation, particularly in the context of Erk1/2 pathway activation, is well described. However, we report that p38 family mitogen-activated protein kinases (namely p38α/Mapk14 and p38β/Mapk11; referred to as p38-Mapk14/11) also participate in PrE formation. Specifically, functional p38-Mapk14/11 are required, during early-blastocyst maturation, to assist uncommitted ICM cells, expressing both EPI and earlier PrE markers, to fully commit to PrE differentiation. Moreover, functional activation of p38-Mapk14/11 is, as reported for Erk1/2, under the control of Fgf-receptor signalling, plus active Tak1 kinase (involved in non-canonical bone morphogenetic protein (Bmp)-receptor-mediated PrE differentiation). However, we demonstrate that the critical window of p38-Mapk14/11 activation precedes the E3.75 timepoint (defined by the initiation of the classical 'salt and pepper' expression pattern of mutually exclusive EPI and PrE markers), whereas appropriate lineage maturation is still achievable when Erk1/2 activity (via Mek1/2 inhibition) is limited to a period after E3.75. We propose that active p38-Mapk14/11 act as enablers, and Erk1/2 as drivers, of PrE differentiation during ICM lineage specification and segregation.
在小鼠胚胎植入前发育过程中，经典的第二次细胞命运决定涉及多能外胚层（EPI）中原始内胚层（PrE）的特化和分离。成纤维细胞生长因子（Fgf）信号在 PrE 分化中的积极作用，特别是在 Erk1/2 途径激活的情况下，已有很好的描述。然而，我们报告说，p38 家族有丝分裂原激活的蛋白激酶（即 p38α/Mapk14 和 p38β/Mapk11；称为 p38-Mapk14/11）也参与 PrE 的形成。具体来说，在早期囊胚成熟过程中，功能性的 p38-Mapk14/11 需要协助表达 EPI 和早期 PrE 标志物的未分化 ICM 细胞完全向 PrE 分化。此外，正如报道的 Erk1/2 一样，p38-Mapk14/11 的功能激活受 Fgf 受体信号以及活性 Tak1 激酶（参与非经典骨形态发生蛋白（Bmp）受体介导的 PrE 分化）的控制。然而，我们证明 p38-Mapk14/11 的关键激活窗口先于 E3.75 时间点（由相互排斥的 EPI 和 PrE 标志物的经典“盐和胡椒”表达模式的起始定义），而当 Erk1/2 活性（通过 Mek1/2 抑制）限制在 E3.75 之后的一个时期时，适当的谱系成熟仍然是可行的。我们提出，活性 p38-Mapk14/11 作为 ICM 谱系特化和分离过程中 PrE 分化的促进剂，而 Erk1/2 作为驱动剂。
