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K. Ranganath, J. Roger, A. Hiriyanna, S. Veleri, R. Cojocaru, L. Zhao, W. T. Wong, R. Bush, A. Swaroop; A Detailed Analysis of the Transient Photoreceptor Degeneration in the Cone-Only Nrl-Knockout Mouse Retina. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4051.
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© ARVO (1962-2015); The Authors (2016-present)
NRL (Neural Retina Leucine Zipper) is a bZIP transcription factor necessary and sufficient for rod photoreceptor differentiation. The deletion of Nrl in mice results in a cone-only retina, with complete transformation of rod precursors to cones. Nrl knockout (Nrl-/-) mice are widely used due to their distinctive phenotype; however the detailed onset and pattern of cone degeneration has not been reported. This study aims to evaluate age-associated changes in the Nrl-/- retina and possible use of these mice as a model for cone degeneration.
The morphology of the aging retina of Nrl-/- mice was evaluated by histology, immunohistochemistry, and TUNEL assays. Cone function was assessed by ERG. Microarray analysis using Affymetrix was performed using retina from 1M, 2M, 4M, 6M, and 10M old Nrl-/- mice.
As Nrl-/- mice age, the thickness of the ONL decreases with maximum cell death occurring between 2-4 M. The ERG response drops in the same timeframe but levels out after 4M; subsequently the ONL thins to a 4-nuclei thickness and the characteristic rosettes disappear. Between 2-4M retinal microglia also migrate to the subretinal space and attain an activated morphology. After 4M, TUNEL staining disappears and retinal microglia return to the inner retina where they recover their resting morphology. Müller cells are activated at all ages examined, as shown by GFAP immunoreactivity. At 10M the remaining cones express S-opsin and M-opsin, contain shortened outer segments, and display a preserved scotopic ERG. Microarray analysis done across multiple stages of degeneration identified a set of misregulated genes early on, and will help elucidate possible mechanisms of cone cell death.
These findings provide a detailed assessment of retinal changes in Nrl-/- mice; cone cell death occurs rapidly between 2-4M after which the retina stabilizes. The retinal degeneration (RD) observed in Nrl-/- mice is unusual in that degeneration does not continue indefinitely as in other RD lines. The Nrl-/- retina is potentially useful for understanding mechanisms underlying cone degeneration and for exploring therapeutic strategies that sustain or replace cone loss in human disease.
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