The ultimate aim of this grant is to identify and modify the regulatory factors of the human fetal keratinocyte prior to commitment toward organ development and terminal differentiation. Human fetal skin will be transplanted to nude mice where the normal human developmental sequence can be evaluated and modified. In addition in-vitro fetal keratinocyte culture systems will be developed to identify mechanisms and modifiers of keratinocyte growth and differentiation which may differ between fetal and adult keratinocytes. By using these two systems, organ development and terminal differentiation of human fetal skin will be studied. By chemically manipulating human fetal epidermal development in both systems, the biological and biochemical responses of fetal keratinocytes during development will be studied. Once the normal process of fetal development is detailed in both systems, major perturbations will be introduced through recombinant grafts of epidermal and dermal tissues and eventually keratinocytes and fibroblasts. These grafts will be modulated by previously identified chemical mediators including 13-cis-retinoic acid. The inductive influences of development will be identified in detail. The inductive influences then will be applied to diseases of epidermal proliferation (ichthyosis, ectodermal dysplasia, psoriasis, epidermal nevi) and diseases of the dermal-epidermal junction (epidermolysis bullosa). Using combinations of mature, fetal and diseased tissues, analysis of disease-induced variations will be evaluated. Modifications of human fetal development by diseased tissues will identify abnormalities of cellular control in disease.