During development, the transcription factor YAP1 is crucial in maintaining proliferation and dedifferentiation of progenitors, as organ and tissue fields are formed. As cells expand to fill developing fields, their cell-cell contacts trigger activation of the Hippo kinase cascade, which causes YAP1 to bind forming tight junctions at the cell surface, thereby preventing its entry into the nucleus. This cytoplasmic sequestration is then necessary for post-mitotic differentiation. Downregulation of tight junction genes in cancer leads to constitutive nuclear translocation of YAP1, where it acts as an oncogene to drive proliferation and the dedifferentiating EMT responsible for carcinoma invasion and metastasis. In an analogous fashion, disruption of RPE cell-cell contacts also allows nuclear translocation of YAP1, leading to EMT and a proliferative, myofibroblastic phenotype responsible for PVR. These findings imply that YAP1 drives a dedifferentiating EMT in the nucleus, and its Hippo-dependent interaction with tight junctions at the cell surface then represents a mean to block its activity. But, there is emerging evidence that, when sequestered in tight junctions at the cell surface, YAP1 binds to the Wnt pathway transcription factor ?-catenin. This interaction appears to prevent ?-catenin nuclear localization and to cause its ubiquitin-mediated turnover. These findings raise the possibility that cytoplasmic YAP1 might have a hitherto unanticipated function to negatively regulate Wnt/?-catenin signaling. This is an interesting possibility because Wnt/?-catenin signaling is linked to maintenance of stem and progenitor cells in an undifferentiated state, and it must be inhibited for differentiation of epithelial cells. Further, reactivation of Wnt/?-catenin signaling (such as when lacking YAP1-mediated inhibition on this pathway) in differentiated epithelial cells drives dedifferentiating EMT and is a hallmark of a highly invasive phenotype for example in colorectal cancer. Based on these emerging findings, we hypothesized that YAP1 has two key functions. The first is to serve as a nuclear transcription factor that drives proliferation, whereas the second function is to actively block Wnt/?-catenin signaling when sequestered at tight junctions and thereby maintain the differentiated phenotype in epithelial cells. By knocking YAP1 out after RPE differentiation, we provide the first evidence that dedifferentiating can be induced by loss of YAP1-mediated restriction of ?-catenin in the cytoplasm for maintaining RPE differentiation. We propose studies to validate this model of YAP1-dependent oscillation between differentiation and dedifferentiation.
The retinal pigment epithelium plays a critical role for physically and physiologically supporting photoreceptors and visual function; and dysfunction of RPE cells has been linked to many retinal diseases. We have generated an RPE-specific Yap1 knockout mouse line and identified the novel functions of YAP1 in maintenance of a healthy RPE differentiation state and in regulation of Wnt/?-catenin signaling pathways. This innovating work allows us a better understanding of how the RPE cells maintain their cell-type-specific differentiated phenotypes, and to uncover pathologic mechanisms causing many vision-threatening RPE- related ocular diseases, such as Sveinsson's chorioretinal atrophy, which will be ultimately beneficial to development of novel therapeutics for treating RPE involved eye diseases.
