Abstract
The nuclear receptor NR2E3 promotes expression of rod photoreceptor genes while repressing cone genes. Mice lacking NR2E3 (Nr2e3rd7/rd7 referred to here as rd7) are a model for enhanced S-cone syndrome, a disease associated with increased sensitivity to blue light and night blindness. Rd7 retinas have reduced levels of the outer segment (OS) structural protein retinal degeneration slow (RDS). We test the hypothesis that increasing RDS levels would improve the Rd7 phenotype. Transgenic mice over-expressing normal mouse peripherin/RDS (NMP) in rods and cones were crossed onto the rd7 background. Disease phenotypes were assessed in NMP/rd7 eyes and compared to wild-type (WT) and rd7 eyes at postnatal day 30. NMP/rd7 retinas expressed total RDS (transgenic and endogenous) message at WT levels, and NMP protein was correctly localized to the OS. NMP/rd7 retinas have shorter OSs compared to rd7 and WT and significantly reduced number of rosettes. NMP/rd7 mice also exhibited significant deficits in scotopic ERG amplitudes compared to rd7 while photopic amplitudes remained unaffected. Protein levels of rhodopsin, RDS, and the RDS homologue ROM-1 were significantly reduced in the NMP/rd7 retinas compared to rd7. We show that correcting the levels of RDS gene expression does not improve the phenotype of the rd7 suggesting that RDS deficiency is not responsible for the defect in this model. We suggest that the specific rod defect in the NMP/rd7 is likely associated with ongoing problems in the rd7 that are related to the expression of cone genes in rod cells, a characteristic of the model.
Highlights
Retinal development and photoreceptor differentiation is guided by a precisely regulated series of transcription factors
Expression and localization of normal mouse peripherin/RDS (NMP) in the rd7 retina To test the hypothesis that increasing retinal degeneration slow (RDS) levels in rd7 retinas could ameliorate the degenerative phenotype, we crossed the NMP transgenic line onto the rd7 background
The difference was not statistically significant, mean photopic b-wave amplitudes in response to green light tended to be lower in rd7 and NMP/rd7, consistent with the modest reduction in M-opsin levels we observed. These results show that a significant rod-targeted functional defect accompanies the structural and biochemical defects which occur in the NMP/rd7 when compared to WT or rd7
Summary
Retinal development and photoreceptor differentiation is guided by a precisely regulated series of transcription factors. The homeobox genes CRX and OTX regulate both rod and cone genesis. Downstream of these are NRL and NR2E3 ( called PNR) [1]. Mutations in the NR2E3 gene are associated with enhanced S-cone syndrome (ESCS) in patients [7] which manifests as increased sensitivity to blue light (mediated by Scones), and night blindness (due to rod defects). Other phenotypes associated with ESCS can include some loss of L- and M-cone vision, as well as retinal tearing and retinal neovascularization [7,8,9]. Mutations within NR2E3 are associated with other retinal diseases, including Goldman-Favre syndrome, clumped pigmentary retinopathy, and autosomal dominant retinitis pigmentosa (ADRP) [10,11,12,13,14]
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