We have examined the protocadherin (Pcdh) gene clusters of the zebrafish (Danio rerio). At least three sets of the Pcdh gene cluster were found in the zebrafish genome. Here, we describe the complete organization of the DrPcdh2 gene clusters. Classification by phylogenetic and transcript analyses revealed 7 DrPcdh2, 20 DrPcdh2alphaa, 12 DrPcdh2alphab, and 1 DrPcdh2alphac variable exons upstream of the DrPcdh2alpha constant region exons in the DrPcdh2 gene cluster. The constant regions of the DrPcdh1alpha and DrPcdh2alpha genes in zebrafish were orthologs of those of the mammalian Pcdhalpha. These exons all encoded plural PXXP motifs in their cytoplasmic tails. The sequences of the variable exons were highly conserved within each family: DrPcdh2, DrPcdh2alphaa, and DrPcdh2alphab. Transcript analysis revealed that zebrafish Pcdhs had alternatively spliced variants in the constant region that were not found in mammals. More gene clusters, more variable exons, and more alternative splicing variants were found in zebrafish than in mammals. Thus, although the Pcdhalpha families were common to diverse vertebrates, their gene number, structure, and transcripts were different between teleosts and mammals. (C) 2004 Elsevier B.V. All rights reserved.