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Stephen Bravo, Toshihide Kurihara, Peter D. Westenskow, Edith Aguilar, Martin Friedlander; Retinal Degeneration is Significantly Accelerated in Dark Reared Animals in a Novel Murine Model of Age-related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4763.
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Age-related macular degeneration (AMD) is one of the leading causes of incurable blindness in industrialized countries and can be caused by retinal pigment epithelium (RPE) dysfunction or death. We have recently developed a novel murine model of AMD in which inducible von Hippel-Lindau (VHL) gene deletion in the adult retinal pigment epithelium (RPE) leads to the onset of retinal degeneration closely resembling human AMD. VHL regulates critical oxygen sensing molecular pathways in multiple ocular tissues, and hypoxic metabolism tolerance can be impaired in the elderly. RPE cells perform critical functions including phagocytosis of shed photoreceptor outer segments and maintenance of the visual cycle. Typically, inherited retinal degenerations in animal models can be slowed by restricting their exposure to light. Excessive light exposure induces retinal degeneration, even in wild-type animals. Therefore, we examined the dynamics of retinal degeneration in dark-reared VHL mutants.
Doxycycline injections in inducible VMD2-Cre mice activate Cre recombinase activity specifically in RPE cells in a mosaic pattern. VMD2-Cre mice were crossed with VHLflox/flox mice to inactivate VHL expression in RPE cells. We inactivated VHL only in adult mice to serve as a model of AMD. The RPE and retinal phenotypes were examined using immunohistochemistry on cryosections, and confocal and electron microscopy. TUNEL assay was performed to confirm apoptosis in specific retinal cell types.
Light reared VHL-/- mice exhibit significant photoreceptor degeneration 28 days after VHL gene deletion in the RPE, and long term VHL deletion (after 8 months) shows catastrophic retinal degeneration. In contrast, dark reared VHL-/- mice showed significant degeneration only 3 days after VHL inactivation, and severe degeneration 14 days post inactivation. TUNEL-positive photoreceptor cells were detected in both light and dark reared mice.
Mice reared in the dark prior to RPE specific VHL gene deletion display dramatically accelerated and pronounced retinal degeneration when compared to VHL mutant mice maintained in conventional light-dark cycles. We will discuss potential mechanisms underlying these observations and their potential application to better understand human AMD pathology.
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