Title:
Mechanisms of position-dependent specification of cell fates in preimplantation embryos

Yoshikazu Hirate, Ph.D.
Department of Cell Fate Control
Institute for Molecular Embryology and Genetics
Kumamoto University

Abstract:
In preimplantation mouse embryos, specification of cell fates into the trophectoderm (TE) or inner cell mass (ICM) depends on the positions of the cell within the embryos. The transcription factor Tead4 is required for specification of the TE fate . Tead4 is present in the nuclei of all blastomeres. Cell-position-dependent Hippo signaling controls nuclear localization of the coactivator protein Yap as well as the activity of Tead4: inactive Hippo signaling in the outer cells increases nuclear Yap levels, activates Tead4, and promotes TE development; on the other hand, active Hippo signaling in the inner cells suppresses nuclear Yap levels, inactivates Tead4, and promotes ICM development. In this study, we show that cell polarity and cell-cell adhesion together establish position-dependent Hippo signaling at approximately the 32-cell stage. Cell-cell adhesion activates Hippo signaling, but polarity in the outer cells suppresses it. The junction-associated protein Angiomotin (Amot) is essential for activation of the Hippo pathway. In the inner cells, Amot localizes to the adherens junctions and activates the Hippo pathway, whereas in the outer cells, cell polarity sequesters Amot from basolateral membranes to apical domains, thus suppressing the Hippo signal. We propose that cell polarity uncouples cell-cell adhesion and the Hippo pathway by sequestering Amot from the adherens junctions. This mechanism converts positional information into determination of the cell-fate through differential Hippo signaling.