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. 2025 Jul 31.
doi: 10.1007/s12035-025-05239-z. Online ahead of print.

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

Cathy M McLeod  1 , Hannah G Lanthier  1 , Garrett R Nitschke  1 , Samjhana Bhandari  1 , Angel C Humphries  1 , Andrew M Garrett  2   3
Affiliations

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

Cathy M McLeod et al. Mol Neurobiol. .

Abstract

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.

Keywords: Apoptosis; G-Protocadherin; Mouse; Neural development; Retina.

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Conflict of interest statement

Declarations. Ethics Approval: Studies involving animals were performed in accordance with The Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee at Wayne State University under protocol numbers 21–07-3772 and 24–06-6953. Competing Interests: The authors declare no competing interests.

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