Clustered protocadherin <i>cis</i>-interactions are required for combinatorial cell-cell recognition underlying neuronal self-avoidance.

Abstract

In the developing human brain, only 53 stochastically expressed clustered protocadherin (cPcdh) isoforms enable neurites from individual neurons to recognize and self-avoid while simultaneously maintaining contact with neurites from other neurons. Cell assays have demonstrated that self-recognition occurs only when all cPcdh isoforms perfectly match across the cell boundary, with a single mismatch in the cPcdh expression profile interfering with recognition. It remains unclear, however, how a single mismatched isoform between neighboring cells is sufficient to block erroneous recognitions. Using systematic cell aggregation experiments, we show that abolishing cPcdh interactions on the same membrane (<i>cis</i>) results in a complete loss of specific combinatorial binding between cells (<i>trans</i>). Our computer simulations demonstrate that the organization of cPcdh in linear array oligomers, composed of <i>cis</i> and <i>trans</i> interactions, enhances self-recognition by increasing the concentration and stability of cPcdh <i>trans</i> complexes between the homotypic membranes. Importantly, we show that the presence of mismatched isoforms between cells drastically diminishes the concentration and stability of the <i>trans</i> complexes. Overall, we provide an explanation for the role of the cPcdh assembly arrangements in neuronal self/non-self-discrimination underlying neuronal self-avoidance.