Protocadherin γC4 Promotes Neuronal Survival in the Mouse Retina Through Its Variable Cytoplasmic Domain

Developmental apoptosis is an important mechanism for the formation of functional neural circuits. Distinct neuronal subtypes undergo apoptosis to a greater or lesser extent during development, although how this is regulated at the cell type level is unknown. The clustered protocadherins (cPcdhs) are ~ 60 homophilic cell adhesion molecules expressed from three contiguous gene clusters, which together encode the α-, β-, and γ-Pcdh families. Only one cPcdh isoform, γC4, is essential for survival in the mouse, given its role in attenuating the extent of developmental neuronal apoptosis. However, there is also evidence that other isoforms contribute to neuronal survival. Here, we focused on amacrine cell types in the mouse retina, using a series of genetic models to ascertain that γC4 alone accounts for the pro-survival function of the γ-Pcdhs, and that neuronal subtype dependence on γ-Pcdhs for survival correlates with expression of this single isoform. To test which domains of the protein were essential for this function, we employed a rescue approach with in vitro live cell imaging, finding that the unique variable cytoplasmic domain of γC4-not its adhesive extracellular cadherin repeats-is necessary and sufficient to promote neuronal survival.