LIGANDS AND ACTIVATORS OF NUCLEAR HORMONE RECEPTORS REGULATE EPIDERMAL DIFFERENTIATION DURING FETAL-RAT SKIN DEVELOPMENT

Because a protective barrier is essential for life, the development of the epidermis and stratum corneum must be completed prior to birth, T he epidermal permeability barrier is comprised of corneocytes embedded in a lipid enriched matrix, Recent studies from our laboratory, using an explant model of fetal rat skin development that closely parallels in utero development, have shown that hormones and other activators o f members of the nuclear receptor family regulate permeability barrier ontogenesis by stimulating lipid metabolism and the formation of the extracellular Lipid lamellae, Using this model we sought to determine whether these hormones and nuclear activators also regulate keratinocy te differentiation during fetal development, Profilaggrin/filaggrin an d loricrin expression, assessed by in situ hybridization and by immuno histochemistry, were progressively increased during epidermal ontogene sis, Whereas profilaggrin/filaggrin and loricrin were not expressed at day 17 of gestation, by day 19 both were present in the upper layers of the epidermis and both became still more abundant by day 21, These developmental changes also occurred in fetal skin explants cultured in vitro for 4 d, although the expression levels did not appear as robus t as in utero, Whereas neither profilaggrin/filaggrin nor loricrin wer e expressed in control explants cultured for 2 d, they were seen in ex plants treated with either thyroid hormone, glucocorticoids, or estrog ens, Tn contrast, dihydrotestosterone treatment delayed the expression of profilaggrin/filaggrin and loricrin, Moreover, both clofibrate, a peroxisome proliferator-gctivated receptor-a ligand, and juvenile horm one III, a farnesoid X-activated receptor activator, markedly accelera ted fetal epidermal differentiation, stimulating both profilaggrin/fil aggrin and loricrin expression. Our results demonstrate that several h ormones and activators of nuclear hormone receptors regulate epidermal differentiation during fetal development, affecting key constituents of both keratohyalin granules and the cornified envelope, Thus, a vari ety of ligands/activators of nuclear receptors accelerate not only per meability barrier ontogenesis, but also the expression of structural p roteins essential for stratum corneum formation.