Abstract
Purpose :
PROM1 is a pentaspan transmembrane glycoprotein localized on the nascent photoreceptor discs. Mutations in Prom1 are associated with multiple retinal diseases, including Retinitis Pigmentosa, Stargardt Disease, and Cone-Rod Dystrophy. Animals lacking PROM1 lose photoreceptors and vision, phenocopying the patient phenotype. Interestingly, raising the PROM1 knockout animals in the dark, protected cell loss and preserved vision. We wanted to investigate the mechanisms behind the protection observed with the hopes of devising novel treatments for PROM1-related visual ailments.
Methods :
In this study, we used two mouse models available from Jackson Labs, rd19 and prom1-creERT2 (prom1-/-). Rd19 animals from Jax labs were in C57Black6/J background; therefore, they were hypomorphic for RPE65 with Methionine at position 450. We backcrossed rd19 to 129SVE/J to generate the RPE65 allele that codes for Leucine at position 450. We measured photoreceptor response via electroretinography (ERG) throughout their post-natal (P) development (P12-P250). We also tested visual function in dark-reared animals to assess if PROM1-mediated degeneration is light-dependent. In all experiments, wild-type littermates were used as controls.
Results :
Our results show that PROM1 is required for vision. There is a significant reduction in photoreceptor response in the absence of PROM1 in all ages from P12 -P250 (p-value<0.001). At P12, there is an approximately two-fold reduction (p-value=9.28x10-4) in scotopic photoreceptor response in prom1-/- animals compared to their wild-type littermates. To our surprise, dark-rearing did not protect photoreceptor degeneration or subsequent vision loss, irrespective of the animal model used or the RPE65 background.
Conclusions :
PROM1 is essential for proper photoreceptor development and visual acuity. Impaired photoreceptor response in the animals lacking PROM1 starts as early as P12 and remains stationary. Dark protection does not reverse the vision impairment caused by the absence of PROM1. Our results signify that PROM1 is not only required for healthy vision but also critical for the normal development of photoreceptors.
Note: SY and SR contributed equally to this work.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.