Gamma-protocadherin homophilic interaction and intracellular trafficking is controlled by the cytoplasmic domain in neurons.

Gamma-protocadherins (Pcdh-gammas) are good candidates to mediate specificity in synaptogenesis but their role in cell-cell interactions is a matter of debate. We proposed that Pcdh-gammas modify preformed synapses via trafficking of Pcdh-gammas-containing organelles, insertion into synaptic membranes and homophilic transcellular interaction. Here we provide evidence in support of this model. We show for the first time that Pcdh-gammas have homophilic properties and that they accumulate at dendro-dendritic and axo-dendritic interfaces during neuronal development. Pcdh-gammas are maintained in a substantial mobile intracellular pool in dendrites and cytoplasmic deletion shifts the molecule to the surface and reduces the number and velocity of the mobile packets. We monitored Pcdh-gamma temporal and spatial dynamics in transport organelles. Pcdh-gamma organelles bud and fuse with stationary clusters near synapses. These results suggest that Pcdh-gamma-mediated cell-cell interactions in synapse development or maintenance are tightly regulated by control of intracellular trafficking via the cytoplasmic domain.