Jedrusik Agnieszka, Cox Andy, Wicher Krzysztof B, Glover David M, Zernicka-Goetz Magdalena
Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Site, Cambridge CB2 3DY, UK.
Department of Genetics, University of Cambridge, Downing Site, Cambridge CB2 3EH, UK.
Dev Biol. 2015 Feb 15;398(2):147-52. doi: 10.1016/j.ydbio.2014.12.004. Epub 2014 Dec 13.
The first lineage segregation in the mouse embryo generates the inner cell mass (ICM), which gives rise to the pluripotent epiblast and therefore the future embryo, and the trophectoderm (TE), which will build the placenta. The TE lineage depends on the transcription factor Cdx2. However, when Cdx2 first starts to act remains unclear. Embryos with zygotic deletion of Cdx2 develop normally until the late blastocyst stage leading to the conclusion that Cdx2 is important for the maintenance but not specification of the TE. In contrast, down-regulation of Cdx2 transcripts from the early embryo stage results in defects in TE specification before the blastocyst stage. Here, to unambiguously address at which developmental stage Cdx2 becomes first required, we genetically deleted Cdx2 from the oocyte stage using a Zp3-Cre/loxP strategy. Careful assessment of a large cohort of Cdx2 maternal-zygotic null embryos, all individually filmed, examined and genotyped, reveals an earlier lethal phenotype than observed in Cdx2 zygotic null embryos that develop until the late blastocyst stage. The developmental failure of Cdx2 maternal-zygotic null embryos is associated with cell death and failure of TE specification, starting at the morula stage. These results indicate that Cdx2 is important for the correct specification of TE from the morula stage onwards and that both maternal and zygotic pools of Cdx2 are required for correct pre-implantation embryogenesis.
小鼠胚胎中的第一次谱系分离产生了内细胞团（ICM），它会发育成多能性上胚层，进而发育成未来的胚胎；还有滋养外胚层（TE），它将构建胎盘。TE谱系依赖于转录因子Cdx2。然而，Cdx2最初何时开始发挥作用仍不清楚。合子缺失Cdx2的胚胎在囊胚晚期之前发育正常，这表明Cdx2对TE的维持很重要，但对其特化并不重要。相比之下，从胚胎早期阶段下调Cdx2转录本会导致在囊胚阶段之前TE特化出现缺陷。在这里，为了明确确定Cdx2在哪个发育阶段首次成为必需，我们使用Zp3-Cre/loxP策略从卵母细胞阶段开始对Cdx2进行基因敲除。对大量Cdx2母源-合子缺失胚胎进行仔细评估，所有胚胎都进行了单独拍摄、检查和基因分型，结果显示其致死表型比发育到囊胚晚期的Cdx2合子缺失胚胎出现得更早。Cdx2母源-合子缺失胚胎的发育失败与细胞死亡和TE特化失败有关，从桑椹胚阶段就开始了。这些结果表明，从桑椹胚阶段起，Cdx2对TE的正确特化很重要，并且Cdx2的母源和合子来源对于正确的植入前胚胎发育都是必需的。
