Roles and Regulation of the Hippo Signaling Pathway in Mammalian Preimplantation Development

During preimplantation development, mammalian embryos form blastocysts. Studies in mouse embryos have revealed multiple roles of the Hippo signaling pathway in this process. Among them, the process of TEA domain transcription factor 4 (TEAD4)-Yes-associated protein (YAP) control of trophectoderm (TE) and inner cell mass fate is the most extensively characterized. The major mechanism of YAP regulation is the activation of Hippo signaling by adherens junctions and inhibition by cell polarization or the apical domain. Several additional mechanisms further modulate Hippo signaling and/or YAP, including polarity regulation by Rho-associated coiled-coil-containing protein kinase (ROCK) and transcription factor AP-2γ (TFAP2C), angiomotin (AMOT) regulation by Ras homolog (RHO), asymmetric inheritance of the apical domain, mechanical regulation, and glucose metabolism. Hippo signaling also regulates other processes during embryogenesis, including zygotic gene activation by maternal YAP, cell state transition at the 8-cell stage, and maturation and quality control of the epiblast via cell competition. The TE fate regulatory role of the Hippo pathway is evolutionarily conserved among mammalian species, including human and bovine embryos, but some details differ.