Previous genetic studies using full cluster deletion mutants revealed that Pcdhgs are required for neuronal survival, but the underlying mechanism remains elusive. In this study, we generated mice lacking subsets of Pcdhg genes and performed quantitative analyses on specific types of neurons and synapses. Mice lacking C-type Pcdhg isoforms are phenotypically indistinguishable from Pcdhg null mutants, and the cellular and synaptic changes examined in both the spinal cord and retina are essentially identical. By contrast, mice lacking a subset of A-type isoforms are viable and fertile, revealing at least some level of functional redundancy among the alternative Pcdhg isoforms. Molecular and biochemical analyses demonstrate that deletion of C-type isoforms does not appreciably alter the expression or function of the A-type and B-type isoforms, indicating that the C-type isoform knockouts are not simply hypomorphic or dominant negative for Pcdhg function. Furthermore, transcriptome profiling shows that the Pcdh repertoires of the two mutants differ significantly, but no neomorphic Pcdhg variants are generated. Therefore, the loss of function of C-type isoforms themselves is most likely responsible for the identical phenotypes observed in both the C-type isoform knockouts and the Pcdhg null mutants.
