The role and expression of the protocadherin-alpha clusters in the CNS

The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. The family of clustered protocadherins (clustered Pcdh family) is substructured into three distinct gene arrays in mammals: Pcdh-α, Pcdh-β, and Pcdh-γ. These are regulated by multiple promoters and cis-alternative splicing without DNA recombination. Pcdh-α proteins interact with β1-integrin to promote cell adhesion. They also form oligomers with Pcdh-γ proteins at the same membrane sites. During neuronal maturation, Pcdh-α expression is dramatically downregulated by myelination. The clustered Pcdh family has multiple variable exons that differ somewhat in number and sequence across vertebrate species. At the single-cell level, Pcdh-α mRNAs are regulated monoallelically, resulting in the combinatorial expression of distinct variable exons from each allele. These findings support the idea that diversified Pcdh molecules contribute to neural circuit development and provide individual cells with their specific identity.