Can spinal nerve cells survive but still fail to build the connections needed for normal movement?

Details

In mice, 58 cadherin-related protocadherin (Pcdh) genes are arranged in tandem in three clusters—alpha, beta, and gamma—on chromosome 18. The large number of clustered Pcdh family members, their presence at synapses, and the known binding specificities of other cadherin superfamily members suggest that these proteins help specify synaptic connectivity.

Mice lacking all 22 genes in the Pcdh-gamma cluster have fewer spinal cord synapses and are nearly immobile. However, interpreting this phenotype was complicated because losing Pcdh-gamma also caused many spinal interneurons to undergo apoptosis, or programmed cell death.

In this experimental genetic study, researchers used two approaches to circumvent apoptosis and neurodegeneration in Pcdh-gamma mutant mice. First, they analyzed mutants lacking both Pcdh-gamma proteins and Bax, a protein that promotes apoptosis. Second, they generated a hypomorphic Pcdh-gamma allele—a version with reduced activity—in which apoptosis was minimal.

With both approaches, spinal interneurons were preserved, but the mice still had dramatically fewer spinal cord synapses and profound neurological defects. Synaptic function was also impaired in neurons cultured from the hypomorphic mutants.

The findings provide evidence that gamma-Pcdhs have a direct role in synaptic development. The study also establishes genetic tools for investigating how these proteins contribute to synaptic specificity.