Lu Chi-Wei, Yabuuchi Akiko, Chen Lingyi, Viswanathan Srinivas, Kim Kitai, Daley George Q
Division of Pediatric Hematology and Oncology, Children's Hospital Boston and Dana Faber Cancer Institute, Boston, Massachusetts 02115, USA.
Nat Genet. 2008 Jul;40(7):921-6. doi: 10.1038/ng.173. Epub 2008 Jun 8.
In blastocyst chimeras, embryonic stem (ES) cells contribute to embryonic tissues but not extraembryonic trophectoderm. Conditional activation of HRas1(Q61L) in ES cells in vitro induces the trophectoderm marker Cdx2 and enables derivation of trophoblast stem (TS) cell lines that, when injected into blastocysts, chimerize placental tissues. Erk2, the downstream effector of Ras-mitogen-activated protein kinase (MAPK) signaling, is asymmetrically expressed in the apical membranes of the 8-cell-stage embryo just before morula compaction. Inhibition of MAPK signaling in cultured mouse embryos compromises Cdx2 expression, delays blastocyst development and reduces trophectoderm outgrowth from embryo explants. These data show that ectopic Ras activation can divert ES cells toward extraembryonic trophoblastic fates and implicate Ras-MAPK signaling in promoting trophectoderm formation from mouse embryos.
在囊胚嵌合体中，胚胎干细胞可分化为胚胎组织，但不能分化为胚外滋养外胚层。体外条件下激活胚胎干细胞中的HRas1（Q61L）可诱导滋养外胚层标志物Cdx2的表达，并能产生滋养层干细胞系，将其注入囊胚后可形成胎盘组织嵌合体。Ras-丝裂原活化蛋白激酶（MAPK）信号通路的下游效应分子Erk2，在桑葚胚致密化前的8细胞期胚胎的顶端膜中呈不对称表达。抑制培养的小鼠胚胎中的MAPK信号通路会损害Cdx2的表达，延迟囊胚发育，并减少胚胎外植体的滋养外胚层生长。这些数据表明，异位Ras激活可使胚胎干细胞转向胚外滋养层细胞命运，并提示Ras-MAPK信号通路在促进小鼠胚胎滋养外胚层形成中发挥作用。
