Cloning of human DCC (deleted in colorectal carcinoma, Fearon et al., 1990) showed that it is an immunoglobulin superfamily member homologous to neural cell adhesion molecules (N-CAM). To explore the normal function of this molecule, we have cloned a chicken homologue to DCC (cDCC) and raised an antibody to DCC. cDCC is a protein of 160 kDa with an expression pattern distinct from those of other immunoglobulin family members including N-CAM and Ng-CAM. Transgene expression of cDCC in fibroblasts led to increased cell-cell adhesion. Localization studies in chicken and mouse embryos showed that DCC is expressed in the epithelia of skin, gut, lung, and bladder. In adult, the expression of DCC is limited to the basal layer of stratified epithelium in skin, crypt regions of intestinal villi, and stem cells in mammary duct. Cell aggregation assay using embryonic chicken skin epithelial cells and antibody to DCC showed it is a Ca2+ independent cell adhesion molecule. In epithelial-mesenchymal interactions during feather morphogenesis, antibody to DCC suppressed the formation of dermal condensations and the polarized localization of N-CAM and fibronectin. These results implied that DCC is an epithelial cell adhesion molecule required for mediating critical functions in epithelial-epithelial and epithelial-mesenchymal interactions.