Genetic manipulations of individual Pcdh gene clusters in mice have provided functional evidence that the clustered Pcdhs are required for normal development of the nervous system. Mutations in the Pcdha gene cluster have been reported to result in defects in olfactory sensory neuron axon coalescence and serotonergic axonal arborization as well as behavioral perturbations (Fukuda et al., 2008; Hasegawa et al., 2008; Katori et al., 2009). By contrast, abolishing Pcdhg function leads to neuronal apoptosis and synaptic loss in the spinal cord and retina (Lefebvre et al., 2008; Prasad et al., 2008; Wang et al., 2002b; Weiner et al., 2005). Although these genetic studies have provided interesting insights into the roles of clustered Pcdhs in the nervous system, the functional significance of the diverse isoforms encoded by the three gene clusters is not understood. For example, it is unclear whether individual Pcdh isoforms within each cluster are functionally equivalent, or whether certain isoforms may play distinct roles. The unique and highly conserved genomic organization of Pcdh gene clusters suggests that the isoform diversity and evolutionary diversification of Pcdh genes are central to understanding their function.
