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.
Journal article
Nat Struct Mol Biol
06/2024
31
964 - 976
Transcription Factor AP-2, TEA Domain Transcription Factors, Animals, Transcription Factors, DNA-Binding Proteins, Mice, Humans, Signal Transduction, Cell Lineage, Gene Expression Regulation, Developmental, Muscle Proteins, Embryo, Mammalian, Hippo Signaling Pathway, Protein Serine-Threonine Kinases, Embryonic Development