Protocadherins’ direct role in synaptic development

Joshua Weiner et al. demonstrate that cadherin-related -protocadherins are directly involved in synaptic development. This gene cluster has been suspected to be involved in synaptic specificity, but functional tests of this idea were lacking. Previous research from their group showed that mice lacking the cluster of the three protocadherin (Pcdh) gene clusters ( , , and ) had decreased spinal cord synapses and were nearly immobile, but interpretation of these findings was complicated by the fact that Pcdhloss also led to apoptosis of spinal interneurons. To circumvent this problem, Weiner et al. generated mutant mice lacking both Pcdhproteins and the proapoptotic protein Bax (Pcdhdel/del Bax / ) and mutant mice bearing a hypomorphic allele of Pcdhin which neuronal apoptosis was minimal (Pcdhtr/tr). In both strains, spinal interneurons were successfully preserved, and the researchers were able to examine the spinal neuron synapses without any neurodegeneration. Nevertheless, these mice showed dramatically decreased numbers of spinal cord synapses and profound neurological defects. Additionally, neurons cultured from the hypomorphic mice were found to have defective synaptic function. These genetic results show that Pcdhproteins are involved in synaptic development, paving the way for testing their role in synaptic specificity.