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Heping Xu, Mei Chen, Chang Luo; Age-dependent Development Of Geographic Retinal Atrophy In Ccl2-/-/cx3cr1gfp/gfp Mice. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2236.
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Previous studies have shown that mice deficient in chemokine ccl2 or fracktalkine receptor cx3cr1 develop degenerative retinal lesions when they are aged, and mice deficient in both ccl2 and cx3cr1 develop retinal lesions at a younger age (i.e. 6-week old, Tuo et al. IOVS. 2007), although the underlying mechanism is poorly defined. In this study, we generated a ccl2-/-cx3cr1gfp/gfp mouse strain in the C57BL/6 background. Since the myeloid-derived cells are GFP+, the mice offer many advantages to study immune dysfunctions in age-related retinal degeneration. The aim of the study was to phenotype the clinical and pathological changes in the ccl2-/-cx3cr1gfp/gfp mice.
Ccl2-/-cx3cr1gfp/gfp mice were generated by crossing the ccl2 KO mice and the cx3cr1gfp/gfp mice (both in C57BL/6 background). Mouse genotype was confirmed by PCR. The mice were maintained in a light controlled environment with 12h-day-light cycle (200 lux). In some experiments, mice were exposed to bright light (800~1000 lux, 4h/day) for 6 months (from 2 ~ 8-month old). Clinical investigations, including topic endoscopic fundus imaging (TEFI) and fluorescein angiography were carried out at various time-points (6-week, 3, 4, 6, 9, 12 and 15 months). Retinal pathologies were examined by light and confocal microscopy at 6, 12, and 15 months.
Retinal lesions were not detected in 6-week old ccl2-/-cx3cr1gfp/gfp mice. Patches of whitish/yellowish lesions were observed by TEFI in ~30% of 6-month old mice, and the incidence increased to 100% by 12 months of age. Choroidal neovascularisation was not observed in any mice in fluorescein angiography. Photoreceptor and RPE damages were detected in 40% of mice aged between 12-15 months, and 5% in 6-month old mice in pathological investigations. Patches of RPE damages were further confirmed by confocal microscopy of RPE/choroidal flatmounts. GFP+ macrophages were detected in RPE flatmounts in 6-month old ccl2-/-cx3cr1gfp/gfp mice, and the cell number increases with age. All DKO mice exposed to bright-light developed photoreceptor/RPE atrophy at 8-month old. Atrophic retinal lesions were not observed in control WT mice.
The ccl2-/-cx3cr1gfp/gfp mice age-dependently develop geographic atrophic retinal lesions. The incidence and severity of disease are enhanced by extra light exposure. The mouse is a good human dry-AMD model, and suitable for mechanistic studies and for testing therapeutic compounds.
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