During mouse embryogenesis, embryos undergo dynamic changes from a single cell zygote to a complex embryo with basic organization of adult body plan in a period of 8 to 9 days. To properly create such a complex morphology, communications among cells play important roles to spatially and temporally coordinate behaviors of cells. There are two types of intercellular communications. One is a long range communication mediated by secreted signaling molecules, and this mechanism induces certain tissues/organs and/or control global patterning of the bodies/tissues. The other mechanism is a short range communication mediated by direct cell-to-cell contacts, and this mechanism acts locally to coordinate various cell behaviors which include proliferation, differentiation and locomotion.
Research in our laboratory focuses on such a short range communication especially the one mediated by Hippo signaling pathway. Hippo signaling pathway was originally identified as a tumor suppressor signaling pathway in Drosophila. We and others found that Hippo pathway also plays important roles in mammals. In cultured cells, Hippo signal mediates contact inhibition of proliferation. In the adult tissues, by controlling cell proliferation, Hippo signal controls organ size and suppresses tumor development. In postimplantation embryos, Hippo signal also controls cell proliferation and is essential to establish body plan properly. On the other hand, in preimplantation embryos, Hippo signal controls cell differentiation. By focusing on the Hippo signaling pathway, we will reveal how cells communicate through interactions and how short range communications control embryonic development.
Hippo pathway controls contact inhibition of cell proliferation
(Left) At low cell density, Hippo pathway is inactive because of low cell-cell contacts. Therefore, the coactivator protein Yap (red signals) accumulates to the nuclei and cells proliferate.
(Right) At high cell density, increased cell-cell contacts activates Hippo pathway. The active Hippo signaling suppresses nuclear accumulation of Yap (red signals), and the cells stop proliferation.
Hippo pathway controls cell fates of preimplantation embryos
(Left) In preimplantation embryos, Hippo signal is activated in the inside cells, but is inactive in the outside cells. As a consequence, Yap (green signals) is excluded from the nuclei of the inside cells, while accumulates in the nuclei of the outside cells.
(Right) Nuclear accumulation of Yap in the outside cells increases transcriptional activity of a transcription factor Tead4. In the outside cells, the active Tead4 induces a transcription factor Cdx2 (red signals), which promotes trophectoderm differentiation of the blastomeres.