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J. Roger, J. Chang, K. Ranganath, A. Hiriyanna, A. Swaroop; ADRP-Associated Mutations in NRL Codon 50 or 51 Affect Photoreceptor Survival Under Bright Light Exposure. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5206.
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© ARVO (1962-2015); The Authors (2016-present)
NRL (Neural Retina Leucine zipper) is the key transcription factor necessary and sufficient for rod differentiation in retina. In Nrl-/- mouse retina, rods are transformed to functional S-cones. NRLis a member of the Maf transcription factor family and its activity is regulated by post-translational modifications. Multiple phosphorylated isoforms of NRL are expressed in rod photoreceptors. Previous studies have shown that mutations in NRL codons 50 (S50T) and 51 (P51S) are associated with autosomal dominant retinitis pigmentosa (ADRP). In cultured cells, these mutations alter NRL phosphorylation and lead to increased NRL transcriptional activity. This study was undertaken to create mouse models of human ADRP resulting from S50T and P51S mutations in NRL and elucidate mechanism(s) of photoreceptor cell death.
We generated two transgenic lines expressing mouse pS50T or pP51S under the control of 2.5 kb Nrl promoter. Mice were mated to Nrl knockout mice to generate different background (levels of wild type Nrl). Retinal degeneration was assessed by histology and immunohistochemistry. Electroretinograms (ERG) were performed to assess retinal function. For light exposure experiments, mice were exposed under bright light (10,000 Lux) for one hour, and eyeballs were harvested two weeks later.
We identified founders for each line expressing different amounts of NRL protein. In each case, expression of NRL mutant protein in Nrl knockout mice resulted in the conversion of cones back to rods. The retinas of these mice were indistinguishable from wild type retinas by histology and ERG, demonstrating that these two mutations do not affect essential NRL function during rod differentiation. Under normal laboratory conditions, these two mutations did not lead to retinal degeneration in aged mice (>12 months). However, retinal degeneration was observed after bright light exposure.
Rod differentiation and photoreceptor survival in mice under normal light conditions are not affected by either S50T or P51S mutation. However, the mutant NRL proteins affect rod survival under bright light exposure, suggesting the importance of phosphorylation in controlling NRL function under stress conditions. Further experiments are in progress to delineate the mechanism of photoreceptor cell death.
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