Current understandings of cell specification in early mammalian pre-implantation development are based mainly on mouse studies. The first lineage differentiation event occurs at the morula stage, with outer cells initiating a trophectoderm (TE) placental progenitor program. The inner cell mass arises from inner cells during subsequent developmental stages and comprises precursor cells of the embryo proper and yolk sac 1 . Recent gene-expression analyses suggest that the mechanisms that regulate early lineage specification in the mouse may differ in other mammals, including human 2 – 5 and cow 6 . Here we show the evolutionary conservation of a molecular cascade that initiates TE segregation in human, cow and mouse embryos. At the morula stage, outer cells acquire an apical–basal cell polarity, with expression of atypical protein kinase C (aPKC) at the contact-free domain, nuclear expression of Hippo signalling pathway effectors and restricted expression of TE-associated factors such as GATA3, which suggests initiation of a TE program. Furthermore, we demonstrate that inhibition of aPKC by small-molecule pharmacological modulation or Trim-Away protein depletion impairs TE initiation at the morula stage. Our comparative embryology analysis provides insights into early lineage specification and suggests that a similar mechanism initiates a TE program in human, cow and mouse embryos. Comparative analysis of human, cow and mouse embryos shows that a mechanism involving atypical protein kinase C initiates the trophectoderm program during the morula stage in these three species.

中文翻译：

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在人类、牛和小鼠胚胎中启动保守的滋养外胚层程序


目前对早期哺乳动物植入前发育中细胞规范的理解主要基于小鼠研究。第一个谱系分化事件发生在桑葚胚阶段，外部细胞启动滋养外胚层 (TE) 胎盘祖细胞程序。内细胞团由随后发育阶段的内细胞产生，并包含胚胎本身和卵黄囊的前体细胞 1 。最近的基因表达分析表明，调节小鼠早期谱系规范的机制可能与其他哺乳动物不同，包括人类 2 – 5 和牛 6 。在这里，我们展示了在人类、牛和小鼠胚胎中启动 TE 分离的分子级联的进化保守性。在桑葚胚阶段，外层细胞获得顶端-基底细胞极性，在非接触域表达非典型蛋白激酶 C (aPKC)、Hippo 信号通路效应子的核表达以及 TE 相关因子（如 GATA3）的限制表达，这表明启动 TE 计划。此外，我们证明，通过小分子药理学调节或 Trim-Away 蛋白消耗来抑制 aPKC 会损害桑葚胚阶段的 TE 启动。我们的比较胚胎学分析提供了对早期谱系规范的见解，并表明类似的机制在人类、牛和小鼠胚胎中启动了 TE 程序。对人类、牛和小鼠胚胎的比较分析表明，涉及非典型蛋白激酶 C 的机制在这三个物种的桑葚胚阶段启动了滋养外胚层程序。