Elevated PRDM13 Disrupts Photoreceptor Function and Survival in the Mammalian Retina.

Abstract

PURPOSE: Retinal degeneration is a common cause of blindness, but there is a gap in our understanding of the molecular mechanisms causing degeneration. Dysregulated PRDM13 has been linked to retinal dystrophy, indicating a role for PRDM13 in the retina. PRDM13 knockout studies have shown that PRDM13 specifies amacrine cell fates, but no studies have shown the phenotypic and mechanistic outcomes of its elevated activity in the retina. METHODS: We developed a mouse model to induce aberrant PRDM13 expression in a controlled, time-dependent manner. ERG and histological analyses were performed to determine whether elevated PRDM13 impacted the health and function of the retina. RNA sequencing of retinas with and without elevated PRDM13 defined transcriptional changes in response to PRDM13 activity. Differentially expressed genes were validated by quantitative PCR and western blot. RESULTS: We found that elevated PRDM13 decreases photoreceptor function and survival. Depletion of elevated PRDM13 halted this degenerative phenotype and restored some photoreceptor function. We further uncovered that elevated PRDM13 alters the expression of markers for amacrine subpopulations. Transcriptomic profiling revealed that elevated PRDM13 deregulates genes involved in retinal development, phototransduction, and photoreceptor health. We found downregulation of Prdm1-a photoreceptor marker-and Nr2e3-a key regulator of photoreceptor specification also implicated in retinal dystrophies-as well as effects on NR2E3's direct and indirect targets. CONCLUSIONS: These findings establish a critical role for PRDM13 in retinal health and provide a new model for elucidating the impact of PRDM13 on photoreceptor maturation, maintenance, and function during retinal development.