Desmogleins (Dsgs) and desmocollins (Dscs) belong to a family of Ca2+dependent adhesion molecules known as cadherins, which cooperate to make up the adhesive core of intercellular junctions called desmosomes. Functional inactivation by a variety of insults, including autoimmune antibodies, bacterial toxins and gene mutations leads to human skin disease. Unfortunately, our understanding of the molecular etiology of these disorders is hampered by a lack of fundamental knowledge about the mechanisms by which desmosomal cadherins assemble into adhesion-competent organelles and the molecular machinery that drives this process. Further, the diversity of desmosomal cadherin family members within complex tissues, suggests that they may have functions that transcend their roles in intercellular adhesion. Indeed, our work suggests that the Dsg1 is required for the morphogenesis of epidermis in a manner that does not require its adhesive domain. It is our hypothesis that desmosomal cadherins have both adhesion-dependent and -independent functions that are coordinated during epidermal morphogenesis, differentiation and remodeling. Towards elucidating these functions and the molecular machinery that controls them, we propose: 1) To determine the mechanism of desmosomal cadherin trafficking in living keratinocytes and how Dsgs and Dscs cooperate to establish the adhesive interface, through a combination of live cell imaging and biochemistry coupled with mutational analysis of exocytic machinery. Novel biomimetic surfaces will be generated as functional platforms for evaluating requirements for adhesion and the ability of pathogenic pemphigus antibodies to inhibit adhesion and downstream cellular responses, 2) To determine the mechanism by which armadillo proteins regulate desmosomal cadherin assembly and adhesive function in conjunction with the cytoskeleton, by mutational analysis of protein interactions coupled with functional assessment of the linkage using novel micromechanical sensors, 3) To determine the function of Dsg1 and associated armadillo proteins in epidermal morphogenesis using in vitro, organotypic and mouse grafting models. These experiments promise to provide a model for the human disease striate palmoplantar keratoderma caused by loss of Dsg1, and will lay a foundation for developing treatments for skin diseases that target desmoglein function.