Gamma protocadherins are required for synaptic development in the spinal cord

Abstract

Fifty-eight cadherin-related protocadherin (Pcdh) genes are tandemly arrayed in three clusters (␣, ␤, and ␥) 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-␥ cluster have decreased numbers of spinal cord synapses and are nearly immobile. Interpretation of this phenotype was complicated, however, by the fact that Pcdh-␥ loss also led to apoptosis of many spinal interneurons. Here, we used two methods to circumvent apoptosis and neurodegeneration in Pcdh-␥ mutant mice. First, we analyzed mutants lacking both Pcdh-␥ proteins and the proapoptotic protein Bax. Second, we generated a hypomorphic allele of Pcdh-␥ 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 ␥-Pcdhs in synaptic development and establish genetic tools for elucidating their contribution to synaptic specificity.A s synapses form, their presynaptic and postsynaptic elements become linked by transmembrane adhesion molecules, including members of the Ig and cadherin superfamilies. Some of these adhesion molecules, such as SynCAM, neuroligin, and neurexin, might function primarily to coordinate presynaptic and postsynaptic differentiation, whereas others might contribute to the selectivity with which synaptic connections form between appropriate partners (reviewed in refs. 1-4). The diversity of the Ig and cadherin families and the binding specificities of individual members suggests that they might be involved in both aspects of synaptogenesis. Support for roles in synaptic specificity has recently been obtained for at least five Ig superfamily members, Sidekick-1 and-2 in vertebrates (5), Syg-1 and -2 in worms (6, 7), and DS-CAM in flies (8, 9).Additional attractive candidate synaptic recognition molecules are the nearly 60 cadherin-related protocadherin (Pcdh) genes tandemly arrayed in three clusters on a single chromosome in mammals (10, 11). These clusters, termed Pcdh-␣, -␤, and -␥, each contain multiple ''variable'' exons encoding the extracellular, transmembrane, and proximal cytoplasmic domains of individual isoforms. Within the Pcdh-␣ and -␥ clusters, each variable exon is transcribed from its own promoter and spliced to ''constant'' exons that encode a shared C-terminal domain (12-15). Many neuronal populations express multiple Pcdh genes, and the ␣-and ␥-Pcdh proteins are concentrated at, although not exclusively localized to, synapses (16-19). Together, these features have led to the hypothesis that combinatorial patterns of Pcdh expression promote specific interactions between presynaptic and ...

GABA A transmission is a critical step in the process of triggering homeostatic increases in quantal amplitude

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Phosphorylation of protocadherin proteins by the receptor tyrosine kinase Ret

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