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Access Type
WSU Access
Date of Award
January 2025
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Pharmacology
First Advisor
Andrew Garrett
Abstract
Cell adhesion molecules (CAMs) play a variety of crucial roles in neural circuit formation, with the g-protocadherin family emerging as key regulators during neuronal development. This family of proteins consists of 22 highly related isoforms that form diverse recognition complexes through promiscuous cis-multimerization and homophilic trans-interactions, via their six cadherin like extracellular domains. While g-Pcdhs are known to regulate many aspects of neuronal devel-opment including neuronal survival, synapse formation and dendritic patterning, the specific con-tributions of individual isoforms are poorly understood. Recently, the gC4 isoform has been identi-fied as uniquely essential for postnatal viability and interneuron survival in mice. This study inves-tigates the molecular mechanism through which gC4 regulates neuronal survival as well as dendrit-ic self-avoidance in the retina. We hypothesize that: 1) gC4’s unique protein sequence makes it nec-essary and sufficient for promoting neuronal survival in the mouse retina, 2) gC4 alone cannot support dendritic self-avoidance in starburst amacrine cells, and 3) gC4 interacts with specific bind-ing partners to promote neuronal survival. Using mouse lines with reduced g-Pcdh diversity in-cluding a gC4 knockout (PcdhgC4KO) and gC4-only expressing (Pcdhg1R1/1R1 ) mutants as well as a novel C4-GFP transgenic mouse, we examine the isoform specific requirements of these develop-mental processes. Our findings demonstrate that loss of gC4 alone is sufficient for amacrine cell apoptosis in the retina, without the contribution of any other g-Pcdh isoform. We were able to iden-tify that the variable cytoplasmic domain (VCD) of gC4 was both necessary and sufficient to res-cue apoptosis in PcdhgC4KO retina culture in vitro, and the extracellular cadherin and intracellular constant domains are not required for this function. We next used C4-GFP transgenic retinas at P10, during the period of developmental apoptosis, to identify candidate protein interactors of gC4 involved in apoptosis. Dendritic self-avoidance in starburst amacrine cells of the retina failed when gC4 alone is expressed in Pcdhg1R1/1R1 mutants. However, cell spacing of AC and RGC is undis-turbed in these mutants, indicating that isoform diversity is dispensable for proper neuronal spacing in the retina.
Recommended Citation
Mcleod, Cathy, "The Role Of Protocadherin Γ-C4 In Neuronal Survival And Self-Avoidance In The Mouse Retina" (2025). Wayne State University Dissertations. 4241.
https://digitalcommons.wayne.edu/oa_dissertations/4241