Elevated PRDM13 disrupts photoreceptor function and survival in the mammalian retina.

Degeneration of the retina is key to the pathogenesis of some of the most common causes of blindness, but there continues to be a gap in our understanding of the molecular mechanisms leading to retinal degeneration, which in turn has impeded progress towards effective treatments. PRDM13 has been associated with the development of the retina but little is known about the impact of elevated PRDM13 on the mammalian retina, which has been linked to human retinal disease. Here, we developed a mammalian model to induce PRDM13 expression outside of endogenous levels, in a controlled time-dependent manner. We discovered that systemic overexpression of PRDM13 in the adult mouse preferentially affects the retina and reduces photoreceptor function and survival over time. The removal of excess PRDM13 halted this degenerative phenotype and allowed for some restoration of photoreceptor function. Examination of the transcriptomic profile of the retinas prior to photoreceptor degeneration highlighted that genes involved in retinal development, phototransduction, and photoreceptor health were significantly altered by the overexpression of PRDM13. This model system can now be used to further elucidate the direct and indirect targets of PRDM13 that impact photoreceptor maturation, maintenance and function during mammalian retinal development and over adulthood. Overall design: We generated a novel mouse model that carries a doxycycline (dox) inducible human PRDM13 gene in the Rosa26 safe harbor locus. This approximately 6 kilobase (kb) knock-in contained the EF-1a ubiquitous promoter driving reverse tetracycline-controlled transactivator (rtTA) expression as well as the TRE3G promoter to control expression of PRDM13. Mice carrying this insert (heterozygous) and wildtype littermates were untreated or treated with 2mg/mL dox + 10% sucrose in the drinking water for 72 hours. Neural retinas and the remaining eye cup (RPE, choroid, sclera) were dissected, flash frozen with liquid nitrogen, and RNA was isolated for RNA-sequencing. 3 biological replicates were sent for analysis for each group.