Protocadherins (Pcdhs) are the largest subgroup of the cadherin superfamily of cell adhesion proteins. Of the ~70 Pcdh genes identified in mammalian genomes, over 50 are located in three tightly linked gene clusters (Pcdha, Pcdhb, and Pcdhg) on a single chromosome (Wu and Maniatis, 1999). These clustered Pcdh genes are found exclusively in vertebrates, and are predominantly expressed in the nervous system. Distinct subsets of Pcdh genes are differentially expressed in individual neurons, and enormous cell surface diversity may result from combinatorial expression (Esumi et al., 2005; Kaneko et al., 2006; Kohmura et al., 1998; Wang et al., 2002a). A subset of Pcdhg isoforms have been shown to engage in intercellular interactions that are strictly homophilic (Schreiner and Weiner, 2010). The molecular diversity as well as the binding specificity of clustered Pcdhs has led to the proposal that they provide a synaptic address code for neuronal connectivity, or a single cell barcode for self-recognition and self-avoidance similar to that ascribed to Dscam1 proteins of invertebrates (Junghans et al., 2005; Serafini, 1999; Shapiro and Colman, 1999; Zipursky and Sanes, 2010).
