Abstract
Nuclear hormone receptors play a major role in many important biological processes. Most nuclear hormone receptors are ubiquitously expressed and regulate processes such as metabolism, circadian function, and development. They function in these processes to maintain homeostasis through modulation of transcriptional gene networks. In this study we evaluate the effectiveness of a nuclear hormone receptor gene to modulate retinal degeneration and restore the integrity of the retina. Currently, there are no effective treatment options for retinal degenerative diseases leading to progressive and irreversible blindness. In this study we demonstrate that the nuclear hormone receptor gene Nr1d1 (Rev-Erbα) rescues Nr2e3-associated retinal degeneration in the rd7 mouse, which lacks a functional Nr2e3 gene. Mutations in human NR2E3 are associated with several retinal degenerations including enhanced S cone syndrome and retinitis pigmentosa. The rd7 mouse, lacking Nr2e3, exhibits an increase in S cones and slow, progressive retinal degeneration. A traditional genetic mapping approach previously identified candidate modifier loci. Here, we demonstrate that in vivo delivery of the candidate modifier gene, Nr1d1 rescues Nr2e3 associated retinal degeneration. We observed clinical, histological, functional, and molecular restoration of the rd7 retina. Furthermore, we demonstrate that the mechanism of rescue at the molecular and functional level is through the re-regulation of key genes within the Nr2e3-directed transcriptional network. Together, these findings reveal the potency of nuclear receptors as modulators of disease and specifically of NR1D1 as a novel therapeutic for retinal degenerations.
Highlights
IntroductionGenetic heterogeneity (identical mutations with variable clinical presentation of disease) is a common feature for many Mendelian disorders [1]
Genetic heterogeneity is a common feature for many Mendelian disorders [1]
Complete suppression of rd7 retinal degeneration was observed in outcrosses of B6.Cg-Nr2e3rd7/rd7 mice to AKR/J, CAST/EiJ or NOD.NOH-H2nb1 mice and several modifier loci that were unique for each strain were identified [40]
Summary
Genetic heterogeneity (identical mutations with variable clinical presentation of disease) is a common feature for many Mendelian disorders [1]. While the underlying mechanisms causing such variations are case specific, it is clear that environmental factors, allelic heterogeneity, genetic modifiers, or a combination of these, can have a profound impact in disease expressivity. Genetic modifiers are allelic variants distinct from the disease-causing gene that can alter disease onset, progression or the clinical features for that particular disease [2]. Since genetic modifiers can result in either increasing or reducing disease severity, identification of modifier loci is important for understanding disease pathophysiology, predicting disease progression and developing novel therapeutic strategies. The availability of extensive genomic tools and multiple inbred strains of mouse models provide a unique platform to uncover genetic modifiers that strongly influence phenotypic variation in human disease [15]. Identification of these modifier genes provides powerful and novel therapeutics
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