Gamma protocadherins are required for synaptic development in the spinal cord

Fifty-eight cadherin-related protocadherin (Pcdh) genes are tandemly arrayed in three clusters (alpha, beta, and gamma) on mouse chromosome 18. The large number of clustered Pcdh family members, their presence at synapses, and the known binding specificities of other cadherin superfamily members all suggest that these Pcdhs play roles in specifying synaptic connectivity. Consistent with this idea, mice lacking all 22 genes of the Pcdh-gamma cluster have decreased numbers of spinal cord synapses and are nearly immobile. Interpretation of this phenotype was complicated, however, by the fact that Pcdh-gamma loss also led to apoptosis of many spinal interneurons. Here, we used two methods to circumvent apoptosis and neurodegeneration in Pcdh-gamma mutant mice. First, we analyzed mutants lacking both Pcdh-gamma proteins and the proapoptotic protein Bax. Second, we generated a hypomorphic allele of Pcdh-gamma in which apoptosis was minimal. In both cases, spinal interneurons were preserved but the mice bore dramatically decreased numbers of spinal cord synapses and exhibited profound neurological defects. Moreover, synaptic function was compromised in neurons cultured from the hypomorphs. These results provide evidence for a direct role of gamma-Pcdhs in synaptic development and establish genetic tools for elucidating their contribution to synaptic specificity.