A LIMITED ROLE FOR RETINOIC ACID AND RETINOIC ADD RECEPTORS RAR-ALPHAAND RAR-BETA IN REGULATING KERATIN-19 EXPRESSION AND KERATINIZATION IN ORAL AND EPIDERMAL-KERATINOCYTES

Different types of stratified squamous epithelia-for example, the ''or thokeratinized'' epidermis, the ''parakeratinized'' gingiva, and the ' 'nonkeratinized'' oral lining mucosal epithelia-are formed by intrinsi cally distinct keratinocyte subtypes, These subtypes exhibit character istic patterns of keratin protein expression in vivo and in culture, K eratin 19 is an informative subtype-specific marker because the basal cells of only nonkeratinizing epithelia express K19 in vivo and in cul ture. Epidermal keratinocytes normally do not express K19, but can be induced to do so in culture by retinoic acid (RA). Keratinocyte subtyp es express the retinoic acid receptor (RAR)beta at levels roughly corr elated with their level of K19 expression in culture and their potenti al for forming a nonkeratinized epithelium in vivo, We tested the hypo thesis that the level of RAR beta expressed by a keratinocyte determin es its K19 expression and its form of suprabasal differentiation. Norm al human epidermal and gingival keratinocytes stably overexpressing ei ther RAR beta or RAR alpha were generated by defective retroviral tran sduction. Overexpression of either receptor enhanced the RA inducibili ty of K19 in conventional culture, in that the proportion of the trans ductants becoming K19(+) in response to RA was markedly increased comp ared with controls, The pattern of differentiation of the epithelium f ormed in organotypic culture, assessed by basal K19 and suprabasal K1, K4, and filaggrin expression, however, was unaltered by RAR overexpre ssion, Thus, the susceptibility of keratinocytes to regulation of K19 expression by retinoids is conditional, and levels of neither RAR beta not RAR alpha are limiting to the intrinsic mechanism that specifies alternate differentiation pathways for stratified squamous epithelia.