Hippo signaling in outer and inner cells of the mouse embryo. (A) Hippo signaling patterns inner and outer cell fates in the morula. Yap is found in the cytoplasm in inner cells (where Hippo signaling is active) and in the nucleus in outer cells. In outer cells, Yap together with Tead4 (not depicted) is required for the expression of Cdx2, a transcription factor that promotes TE differentiation. Yap asymmetry is directed by Amot, which is found all around the surfaces of inner cells but only at contact-free surfaces of outer cells. Amot and the interacting protein E-cadherin colocalize only in inner cells. (B) Model for polarity and adhesion-mediated Hippo pathway asymmetry in outer and inner cells. In outer cells, nonphosphorylated Amot interacts with apical actin, Nf2, and Lats, sequestering Lats and preventing Hippo pathway activity. Consequently, Yap is nuclear. In inner cells, phosphorylated Amot complexes with Nf2 and Lats at AJs, leading to Hippo pathway activity and restriction of Yap to the cytoplasm. The model is based on Hirate and Sasaki (2014). P, phosphorylation.