Annexin IV (AIV), a Ca2+-dependent membrane-binding protein, is expressed in many epithelia. Annexin IV modifies membrane bilayers by increasing rigidity, reducing water and H+ permeability, promoting vesicle aggregation, and regulating ion conductances, all in a Ca2+-dependent manner. We have characterized a mouse in which a gene trap has been inserted into the first intron of annexin IV. Processing of the primary transcript is disrupted. Northern blot and immunoblot data indicated that annexin IV expression was eliminated in many but not all tissues. Immunohistochemical analysis, however, demonstrated that annexin IV expression was eliminated in some cell types, but was unaltered in others. 5'-Rapid amplification of cDNA ends analysis of intestinal and kidney RNA revealed three transcripts, AIVa, AIVb, and AIVc. AIVa is widely distributed. AIVb is expressed only in the digestive tract. AIVc expression is very restricted. A selected number of epithelial cells of unique morphology demonstrate high concentrations. All three transcripts produce an identical annexin IV protein. The different tissue and cell-specific expression profiles of the three transcripts suggest that regulation of both the annexin IV gene expression and the cellular role of the protein are complex. The AIVa-/- mouse may become a valuable model to further study transcription and the physiological role of annexin IV.