Functions of the desmosomal cadherin, desmoglein 1, and its cytoplasmic domain binding partners in epidermal differentiation, morphogenesis, and disease

The seven desmosomal cadherins, including desmogleins and desmocollins, form adhesive intercellular junctions called desmosomes, which are crucial for epidermal development and integrity. Expression of these adhesive proteins is initiated at different stages of keratinocyte differentiation, implying they may play non-redundant roles during tissue stratification. Though their ectodomains are similar to other cadherins, the desmoglein intracellular domains extend well beyond the residues conserved in classical cadherins. Thus, more than mediating adhesion, I propose the unique cytoplasmic domains of desmogleins serve as platforms for specific proteins governing epidermal development and homeostasis. Here, I investigated the role of desmoglein 1 (Dsg1) and its cytoplasmic domain binding partners in differentiation, morphogenesis, and disease of human epidermis.;Dsg1 is expressed early in differentiation as keratinocytes stratify, suggesting this cadherin may coordinate signaling and cytoskeletal dynamics during epidermal development. Using gene silencing and replacement, I established that beyond its ability to mediate adhesion, Dsg1 is required for suppressing signaling from the epidermal growth factor receptor (EGFR) and ErbB2 as keratinocytes differentiate. Further biochemical experiments revealed that Dsg1 completes this signaling function through a novel binding partner, Erbin, which regulates ErbB2 signaling. In addition to defective differentiation, Dsg1-deficient organotypic cultures exhibited alterations in suprabasal cell morphology. We found that Dsg1 interacts with an actin modulator, cortactin, and may utilize this cytoskeletal regulator to coordinate morphogenesis of stratifying keratinocytes. Additionally, my studies revealed that Dsg1 regulates cell-matrix interactions during keratinocyte differentiation likely by governing subcellular distribution of plakoglobin (PG).;Finally, I investigated the pathogenic role of ectodomain-truncated Dsg1 in epidermal blistering. Cleavage of Dsg1's ectodomain by exfoliative toxin causes superficial blisters, but the fate of toxin-cleaved Dsg1 and the exact mechanism of blistering remain unclear. My studies indicate that ectodomain-truncated Dsg1 negatively influences adhesion through sequestering PG. Accordingly, increasing PG levels restored adhesion in cells expressing truncated Dsg1 and could suggest novel strategies to limit toxin-induced blistering in patients.;Together, these studies revealed that Dsg1 executes multiple essential roles in the construction of the cutaneous barrier. Through its ability to couple with known and novel binding partners, Dsg1 contributes to both the development and integrity of the epidermis.