Epithelial cells are tightly connected by various kinds of junctions, of which the desmosomes (maculae adhaerentes) are particularly prominent. The desmosomes are characterized by two subgroups of constitutive transmembrane glycoproteins, the desmogleins and the desmocollins, which have been identified as specific members of the larger multigene family of CAMs of the cadherin category. Following our recent observation in bovine tissues that different desmoglein and desmocollin genes can be expressed in different cell types (Koch, P.J. et al., Proc. Natl. Acad. Sci. USA 89:353-357, 1992), we have now isolated cDNAs encoding human desmocollins type 1 and type 2. The complete sequence of human type 1 desmocollin has been determined and identified by its homology to the corresponding bovine gene product. Using in situ hybridization on sections through frozen human tissues, we show that mRNAs for type 2 desmocollin are synthesized in various stratified epithelia such as epidermis, esophagus and exocervix, whereas type 1 desmocollin was detected in appreciable amounts only in epidermis. In addition, a striking difference has been observed within the epidermis, where type 2 desmocollin mRNA can be detected in several basal layers of living cells but type 1 desmocollin mRNA is restricted to suprabasal layers. The possible functional involvement of desmocollins in the differentiation of stratified tissues is discussed and the potential value of molecular probes for desmosomal cadherins in tumor diagnosis is emphasized.