Excess cone cell proliferation due to lack of a functional NR2E3 causes retinal dysplasia and degeneration in rd7/rd7 mice

The rd7 mouse is a model for hereditary retinal degeneration characterized clinically by retinal spotting throughout the fundus and late onset retinal degeneration, and histologically by retinal dysplasia manifesting as folds and whorls in the photoreceptor layer. This study demonstrates that the rd 7 phenotype results from a splicing error created by a genomic deletion of an intron and part of an exon. Hematoxylin/eosin staining of rd7 tissue sho ws that the whorls in the outer nuclear layer of the retina do not appear d uring embryonic development but manifest by postnatal day 12.5 (P12.5). Fur thermore, in situ hybridization data indicates that the Nr2e3 message is fi rst present at barely discernable levels at embryonic day 18.5, becomes abu ndant by P2.5, and reaches maximal adult levels by P10.5. Results from thes e experiments indicate that Nr2e3 message is expressed prior to the develop ment of S-cones. This data coincides with studies in humans showing that mu tations in Nr2e3 result in a unique type of retinal degeneration known as e nhanced S-cone syndrome, where patients have a 30-fold increase in S-cone s ensitivity compared to normal. Immunohistochemical staining of cone cells d emonstrates that rd7 retinas have an increased number of cone cells compare d to wild-type retinas. Thus, Nr2e3 may function by regulating genes involv ed in cone cell proliferation, and mutations in this gene lead to retinal d ysplasia and degeneration by disrupting normal photoreceptor cell topograph y as well as cell-cell interactions.