The vertebrate-specific Pcdh gene cluster shares remarkable resemblance with Drosophila Dscam1 gene in that they both have a complex genomic structure, which encodes a large number of distinct isoforms of cell adhesion molecules with homophilic binding affinity. These parallels have led to the hypothesis that Pcdhs, like Dscams, may provide a source of cell surface diversity for neurite self-recognition and self-avoidance (Zipursky and Sanes, 2010). This possibility is supported by our recent finding of dendritic self-avoidance defects in Pcdhg deficient mice (Lefebvre et al., 2012). A fundamental difference, however, resides in the fact that each Dscam1 isoform appears to be functionally equivalent, whereas certain Pcdhs, such as the C-type isoforms, have unique roles as we show here. Unlike Dscam1 where isoform diversity is generated by alternative splicing, differential expression of Pcdh isoforms is regulated by alternative promoter choice (Tasic et al., 2002; Wang et al., 2002a), which provides precise spatial and temporal controls over gene expression. As noted earlier, the C-type isoforms are phylogenetically unique among Pcdhs and exhibit distinct expression patterns. It remains to be seen whether just one
