Neovascularization, enhanced inflammatory response, and age-related cone dystrophy in the Nrl-/-Grk1-/- mouse retina.
OBJECTIVE
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.
Yetemian
Rosanne M
RM
Doheny Eye Institute, Department of Ophthalmology, Division of Retinal Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033-9224, USA.
Brown
Bruce M
BM
Craft
Cheryl M
CM
D000375:Aging / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D050976:Basic-Leucine Zipper Transcription Factors / Q000502:physiology*; D002470:Cell Survival; D003623:Dark Adaptation; D004596:Electroretinography; D005136:Eye Proteins / Q000502:physiology*; D005451:Fluorescein Angiography; D051606:G-Protein-Coupled Receptor Kinase 1 / Q000502:physiology*; D020868:Gene Silencing / Q000502:physiology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008027:Light; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology* / Q000528:radiation effects; D058499:Retinal Dystrophies / Q000503:physiopathology*; D015861:Retinal Neovascularization / Q000503:physiopathology*; D012173:Retinitis / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D050976:Basic-Leucine Zipper Transcription Factors; D005136:Eye Proteins; C084884:Nrl protein, mouse; D051606:G-Protein-Coupled Receptor Kinase 1; C496762:Grk1 protein, mouse