Promoter Choice in the Protocadherin a Gene Cluster:
The Pcdha cluster is shown and is representative of both Pcdha and g genes. (A)
Transcription of Pcdha genes. Each Pcdh V exon is preceded by its own promoter. Each c-type Pcdha gene is expressed biallelically and in every cell. An additional 1 to 3 non-c-type genes are expressed monoallelically and stochastically. In the example shown, Pcdhac1 and ac2 are expressed biallelically and Pcdha1 and a8 are expressed monoallelically. (B)
Splicing of Pcdha pre-mRNAs. For each Pcdha pre-mRNA, the V exon closest to the 5’ cap is spliced to 3 cluster-specific constant exons. (C)
Translation of Pcdha proteins. Each V exon encodes a variable region consisting of six EC domains, the TM domain and a short stretch of the ICD. The remainder of the ICD is encoded by the three Pcdha Con exons and is referred to as the constant region. The constant region is common to every Pcdha protein. Transcription, splicing and translation of the Pcdhg genes occur in a similar fashion.
We are studying mechanisms of promoter choice in individual neurons, and have identified conserved promoter elements and two transcriptional enhancer elements in the a cluster required for neuron-specific expression. Detailed analysis of protein-DNA interactions, chromatin modifications, DNA methylation and gene expression are in progress.
We are studying the function of protocadherins in cell signaling, and brain function using biochemical and genetic tools. We have shown that protocadherin cleavage at the membrane by g-secretase requires endocytosis, and that protocadherins are assembled at the cell surface in large complexes containing multiple protocadherins, and a wide array of signaling molecules. We have generated a variety of protocadherin cluster deletion mutants in mice, and are analyzing the phenotypes of these mice.