ReviewClustered protocadherin trafficking

The cluster of almost 60 protocadherin genes, divided into the α, β and γ subgroups, is a hallmark of vertebrate nervous system evolution. These clustered protocadherins (Pcdhs) are of interest for several reasons, one being the arrangement of the genes, which allows epigenetic regulation at the cluster and single-cell identity. Another reason is the still ambiguous effect of Pcdhs on cell-cell interaction. Unlike the case for classical cadherins, which typically mediate strong cell adhesion and formation of adherens junctions, it has been challenging to ascertain exactly how Pcdhs affect interacting cells. In some instances, Pcdhs appear to promote the association of membranes, while in other cases the Pcdhs are anti-adhesive and cause avoidance of interacting membranes. It is clear that Pcdh extracellular domains bind homophillically in an antiparallel conformation, typical of adhesive interactions. How can molecules that would seemingly bind cells together be able to promote the avoidance of membranes? It is possible that Pcdh trafficking will eventually provide insights into the role of these molecules at the cell surface. We have found that endogenous and expressed Pcdhs are generally less efficient at targeting to cell junctions and synapses than are classical cadherins. Instead, Pcdhs are prominently sequestered in the endolysosome system or other intracellular compartments. What role this trafficking plays in the unique mode of cell-cell interaction is a current topic of investigation. It is tempting to speculate that modulation of endocytosis and endolysosomal trafficking may be a part of the mechanism by which Pcdhs convert from adhesive to avoidance molecules.