Molecular mechanisms governing Pcdh-γ gene expression: Evidence for a multiple promoter and cis-alternative splicing model

The genomic architecture of protocadherin (Pcdh) gene clusters is remarkably similar to that of the immunoglobulin and T cell receptor gene clusters, and can potentially provide significant molecular diversity. Pcdh genes are abundantly expressed in the central nervous system. These molecules are primary candidates for establishing specific neuronal connectivity. Despite the extensive analyses of the genomic structure of both human and mouse Pcdh gene clusters, the definitive molecular mechanisms that control Pcdh gene expression are still unknown. Four theories have been proposed, including (1) DNA recombination followed by cis-splicing, (2) single promoter and cis-alternative splicing, (3) multiple promoters and cis-alternative splicing, and (4) multiple promoters and trans-splicing. Using a combination of molecular and genetic analyses, we evaluated the four models at the Pcdh-γ locus. Our analysis provides evidence that the transcription of individual Pcdh-γ genes is under the control of a distinct but related promoter upstream of each Pcdh-γ variable exon, and posttranscriptional processing of each Pcdh-γ transcript is predominantly mediated through cis-alternative splicing.