ROR2 regulates Wnt signaling and cell-cell adhesion to govern skin morphogenesis

During skin morphogenesis, Wnt/β-catenin signaling pathway is essential for epidermis stratification and hair follicle formation; however, little is known about the significance of β-catenin-independent Wnt pathways. ROR2 is a Wnt receptor shown to mediate Wnt5a-dependent non-canonical Wnt signaling pathways, which regulate cell migration, cytoskeleton reorganization and planar cell polarity. Very little information can be found about ROR2-dependent regulation in skin morphogenesis. In this doctoral thesis, we generated a conditional knockout model where Ror2 is depleted in basal cells of the developing epidermis. By analyzing Ror2-depleted skin, we discovered that ROR2 is essential for hair follicle induction via the regulation of cell proliferation, cell migration and Wnt/β-catenin signaling activation. Moreover, we also found that ROR2 is important for the maintenance of basal cell polarity and intercellular adhesion, which are essential to keep the organization of epidermis. In identifying the underlying mechanism, we uncovered that overactivation of PKCδ is responsible for the disruption of intercellular adhesions upon Ror2 depletion. Finally, this study not only strengthens the previous findings in ROR2-mediated Wnt signaling, but also we unveiled a previously unrecognized role of ROR2 in modulating cell-cell adhesion that is essential to maintain skin integrity.