The human clustered protocadherin (Pcdh) genes are encoded by three tandem gene clusters (a, b & g) spanning nearly 1 million base pairs of DNA chromosome 5 (5q31). The function of the Pcdh gene cluster is to provide a cell surface “identity code” for individual neurons, which is required for normal neural circuit assembly. This code is generated through a mechanism of stochastic promoter choice and RNA splicing, which generates a combination of distinct protein isoforms that form random cis-dimers at the interface between apposing cell membranes. Stochastic promoter activation occurs through a remarkable mechanism that involves the activation of an anti-sense promoter within the exon of each protein isoform that generates a long non-coding lncRNA that reads through the upstream antisense promoter. This in turn leads to the demethylation of the sense strand promoter, the binding of CTCF/cohesin to both the sense and antisense promoters and to two binding sites in a distal enhancer located over 300Kb away. DNA looping brings the enhancer and promoter together to establish a epigenetically stable promoter choice. Once generated, the cell surface code is “read” through highly specific homophilic interactions between cis-dimers at the interface between apposing membranes. These interactions lead to the formation of a protein lattice between cells as revealed by Cryoelectron tomography. Importantly, this homophilic binding results in repulsion rather that adhesion, thus providing individual neurons the ability to distinguish between self and non-self and to avoid self. Studies of Pcdh gene cluster deletions in mice reveal neuron-type specific defects in neurite self-avoidance and tiling, and behavioral abnormalities. In humans, genetic studies reveal DNA sequence variants that associate with the Pcdh gene cluster in autism, schizophrenia and bipolar disease.
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TITLE:
The Human Clustered Protocadherin Genes Provide a Single Cell Identity Code for Neural Circuit Assembly
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On March 5, 2019 at 4:00 pm till 5:00 pmSPEAKER:
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Broad Institute Auditorium, 415 Main Street