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Published on: December 27, 2015
Neovascularization, enhanced inflammatory response, and age-related cone dystrophy in the Nrl-/-Grk1-/- mouse retina
Rosanne M Yetemian1, Bruce M Brown, Cheryl M Craft
1Doheny Eye Institute, Department of Ophthalmology, Division of Retinal Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033-9224, USA.
Purpose:
The effects of aging and light exposure on cone photoreceptor survival were compared between mouse retinas of neural retina leucine zipper knockout (Nrl(-/-)) mice and double-knockout mice lacking G-protein-coupled receptor kinase 1 (Nrl(-/-)Grk1(-/-)).
Methods:
Mice were reared in total darkness, ambient cyclic light, or constant light, and their retinas were evaluated from 1 to 9 months of age using immunohistochemistry, electroretinography, and fluorescein angiography. Retinal gene expression and statistically significant probe sets were categorized using analysis software. Select gene expression changes were confirmed with quantitative RT-PCR.
Results:
In contrast to retinas from Nrl(-/-), those from Nrl(-/-)Grk1(-/-) exhibit a progressive loss of the outer nuclear layer, retinal physiology deficits, and a higher rate of degeneration with increasing age that is independent of environmental light exposure. Changes in retinal neovascularization occur in the Nrl(-/-)Grk1(-/-) at 1 month, before the onset of significant cone functional deficits. Microarray analyses demonstrate statistically significant changes in transcript levels of more than 400 genes, of which the oncostatin M signaling pathway and the inflammatory disease response network were identified.
Conclusions:
These data demonstrate that the loss of functional Grk1 on the enhanced S-cone Nrl(-/-) background exacerbates age-related cone dystrophy in a light-independent manner, mediated partly through the inflammatory response pathway and neovascularization. According to these findings, Grk1 helps to maintain a healthy cone environment, and the Nrl(-/-)Grk1(-/-) mouse allows examination of the alternative roles of Grk1 in cone photoreceptor homeostasis.
Insights
Loss of G-protein-coupled receptor kinase 1 (Grk1) in neural retina leucine zipper knockout (Nrl(-/-)) mice accelerates age-related cone degeneration. This process is independent of light exposure and involves inflammation and neovascularization.
Area of Science:
- Ophthalmology
- Molecular Biology
- Genetics
Background:
- Cone photoreceptors are crucial for high-acuity color vision.
- Aging and light exposure can impact cone photoreceptor health.
- Neural retina leucine zipper (Nrl) is essential for rod photoreceptor development, and its absence leads to enhanced S-cone development.
Purpose of the Study:
- To investigate the combined effects of aging and light exposure on cone photoreceptor survival.
- To compare cone survival in Nrl knockout (Nrl(-/-)) mice versus double knockout (Nrl(-/-)Grk1(-/-)) mice lacking G-protein-coupled receptor kinase 1 (Grk1).
Main Methods:
- Mice (Nrl(-/-)) and (Nrl(-/-)Grk1(-/-)) were exposed to darkness, cyclic light, or constant light from 1 to 9 months of age.
- Retinas were analyzed using immunohistochemistry, electroretinography, and fluorescein angiography.
- Gene expression profiling (microarray) and quantitative RT-PCR were employed.
Main Results:
- Nrl(-/-)Grk1(-/-) retinas showed progressive outer nuclear layer loss, physiological deficits, and degeneration with age, irrespective of light conditions.
- Retinal neovascularization was observed in Nrl(-/-)Grk1(-/-) mice at 1 month, preceding significant cone dysfunction.
- Microarray analysis revealed significant changes in over 400 genes, highlighting the oncostatin M signaling pathway and inflammatory response network.
Conclusions:
- Loss of functional Grk1 exacerbates age-related cone dystrophy in Nrl(-/-) mice, independent of light.
- Inflammation and neovascularization play partial roles in this Grk1-dependent cone degeneration.
- Grk1 is vital for maintaining cone photoreceptor health, and the Nrl(-/-)Grk1(-/-) model offers insights into Grk1's role in cone homeostasis.
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