E-CADHERIN AND P-CADHERIN HAVE PARTIALLY REDUNDANT ROLES IN HUMAN EPIDERMAL STRATIFICATION

Classical cadherins are Ca2+-dependent homotypic intercellular adhesio n molecules that play major regulatory roles in tissue morphogenesis. Human epidermis, which expresses two classical cadherins (E- and P-cad herins), undergoes continual differentiation and morphogenesis, not ju st during embryonic development, but throughout life. The relative rol es of E- and P-cadherin in epidermal morphogenesis have been studied i n human epidermal keratinocytes in culture. In these cultures, tissue morphogenesis can be initiated simply by elevation of the extracellula r Ca2+ concentration, which activates the cadherins, initiates desmoso me organization, and then induces reorganization of the culture from a monolayer into a multilayered, more differentiated, epithelial-like s tructure. By examination of cultures after several days in high Ca2+, previous data have shown that concurrent inhibition of both E- and P-c adherins nearly abrogates the Ca2+-induced stratification response; ho wever, it has not been possible to discern from these studies whether the two cadherins have unique or redundant regulatory properties. The present study has demonstrated, via electron-microscopic analysis of c ultures at an early stage in stratification, that inhibition of either of the cadherins alone does not affect the initiation of stratificati on, i.e. the formation of up to 2-3 cell layers. Thus, E-cadherin and P-cadherin may have similar regulatory functions with respect to the i nitiation of stratification. However, if stratification is to continue further to produce a tissue-like structure of 5-7 cell layers, then E -cadherin is required and P-cadherin cannot act as a substitute, presu mably because of the distinct localizations of E- and P-cadherins; E-c adherin is found in all cell layers of the stratified epithelium, wher eas P-cadherin is lost after the basal keratinocytes become detached f rom the basement membrane and assume a suprabasal position. Therefore, basal cells, which have two cadherins, can utilize either cadherin to initiate stratification, whereas superficial cells, which have only E -cadherin, are dependent on this cadherin for further stratification.