The mouse and human embryo gradually loses totipotency before diversifying into the inner cell mass (ICM, future organism) and trophectoderm (TE, future placenta). The transcription factors TFAP2C and TEAD4 with activated RHOA accelerate embryo polarization. Here we show that these factors also accelerate the loss of totipotency. TFAP2C and TEAD4 paradoxically promote and inhibit Hippo signaling before lineage diversification: they drive expression of multiple Hippo regulators while also promoting apical domain formation, which inactivates Hippo. Each factor activates TE specifiers in bipotent cells, while TFAP2C also activates specifiers of the ICM fate. Asymmetric segregation of the apical domain reconciles the opposing regulation of Hippo signaling into Hippo OFF and the TE fate, or Hippo ON and the ICM fate. We propose that the bistable switch established by TFAP2C and TEAD4 is exploited to trigger robust lineage diversification in the developing embryo.

小鼠和人类胚胎在分化为内细胞团（ICM，未来有机体）和滋养外胚层（TE，未来胎盘）之前逐渐失去全能性。转录因子 TFAP2C 和 TEAD4 与激活的 RHOA 加速胚胎极化。在这里，我们表明这些因素也会加速全能性的丧失。 TFAP2C 和 TEAD4 在谱系多样化之前矛盾地促进和抑制 Hippo 信号传导：它们驱动多个 Hippo 调节因子的表达，同时也促进顶端结构域的形成，从而使 Hippo 失活。每个因子都会激活双能细胞中的 TE 指定因子，而 TFAP2C 也会激活 ICM 命运的指定因子。顶端域的不对称分离将 Hippo 信号传导的相反调节调和为 Hippo OFF 和 TE 命运，或 Hippo ON 和 ICM 命运。我们建议利用 TFAP2C 和 TEAD4 建立的双稳态开关来触发发育中胚胎中强大的谱系多样化。