Isoform requirement of clustered protocadherin for preventing neuronal apoptosis and neonatal lethality

Clustered protocadherin is a family of cell-surface recognition molecules implicated in neuronal connectivity that has a diverse isoform repertoire and homophilic binding specificity. Mice have 58 isoforms, encoded by Pcdha, beta, and gamma gene clusters, and mutant mice lacking all isoforms died after birth, displaying massive neuronal apoptosis and synapse loss. The current hypothesis is that the three specific gamma C-type isoforms, especially gamma C4, are essential for the phenotype, raising the question about the necessity of isoform diversity. We generated TC mutant mice that expressed the three gC-type isoforms but lacked all the other 55 isoforms. The TC mutants died immediately after birth, showing massive neuronal death, and gamma C3 or gamma C4 expression did not prevent apoptosis. Restoring the alpha- and beta-clusters with the three gamma C alleles rescued the phenotype, suggesting that along with the three gamma C-type isoforms, other isoforms are also required for the survival of neurons and individual mice.

Automated summary

Clustered protocadherin is a family of cell-surface recognition molecules with diverse isoforms and homophilic binding specificity. Mutant mice lacking all 58 isoforms showed massive neuronal apoptosis and synapse loss, raising questions about the necessity of isoform diversity. TC mutant mice expressing only three specific gamma C-type isoforms died immediately after birth, indicating that other isoforms are also required for neuronal survival.