Overexpression of PRDM13 Leads to Photoreceptor Degeneration in a Novel, Inducible Murine Model

Abstract

Purpose : As the primary cells involved in light-sensing, loss of photoreceptor neurons in the retina leads to diminished vision or even complete blindness. Despite rigorous study, there is a lack of knowledge surrounding why and how photoreceptors are lost, in part due to a scarcity of non-genetic, in vivo models of photoreceptor degeneration. Interestingly, a 2018 Developmental Biology paper by Goodson, et al. demonstrated that overexpression of the PR/SET 13 (PRDM13) protein in a murine explant culture led to loss of photoreceptor development. PRDM13 is typically silent in adult tissues but is known to be a transcriptional regulator in the central nervous system during development and is particularly important for defining excitatory vs. inhibitory neural lineages in the dorsal neural tube. Duplications in PRDM13 have also been found in some patients with North Carolina Macular Dystrophy. Thus, we hypothesize that over-expression of PRDM13 does not directly cause photoreceptor degeneration, but rather alters transcriptional regulation of proteins important to photoreceptor survival.

Methods : To address this hypothesis, we have generated a transgenic mouse line with ubiquitous Doxycycline (Dox) inducible overexpression of human (h)PRDM13. We have characterized this novel mouse model via live imaging (electroretinography & scanning laser ophthalmoscopy) to assess functional and structural changes throughout the retina under a low (1 day), mid (6 days), or long (10 days) exposure to Dox beginning at one month of age.

Results : We have discovered that the most severe loss of function occurs in the retinal pigment epithelium and rod photoreceptor cells, within one day of Dox exposure. In both the mid and long Dox exposure groups, cone photoreceptor and inner nuclear layer function is also significantly reduced. Changes to retinal structure are not evident until about a week post-Dox exposure, indicating a loss of function prior to cell death.

Conclusions : Our results demonstrate that overexpression of hPRDM13 leads to photoreceptor degeneration in the murine retina, and that the severity of degeneration is dependent upon how long hPRDM13 is overexpressed. This model will be particularly useful for studying changes in neuronal transcription, cellular crosstalk, and to determine the potential best window of treatment for therapeutics of mild, moderate, and severe stages of photoreceptor degeneration.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.