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Ruilin Zhu, Kin-Sang Cho, Yuan Fang, Christine Xu, Liu Yang, Dong Chen; Absence of ephrin-A2/A3 promotes photoreceptor regeneration in rhodopsin knockout mice. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1166.
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We showed previously that ephrin-A2/A3 are negative regulators of neural progenitor cell proliferation in the mature central nervous system, including retina. Lack of ephrin-A3 enhances the proliferation and differentiation of retinal progenitor cells into photoreceptors in vitro. We hypothesize that absence of ephrin-A2/A3 promotes photoreceptor regeneration and rescue vision loss in rhodopsin knockout (rho-/-) mice.
Photoreceptor morphology and function were examined in wild-type (WT), ephrin-A2-/-A3-/- (A2-/-A3-/-), rho-/-, and rho-/-ephrin-A2-/-A3-/- (rho-/-A2-/-A3-/-) mice. Proliferating retinal progenitor cells in the retina were labeled by injecting BrdU (50mg/kg; i.p.) twice daily for 7 days and revealed by immunolabeling with anti-BrdU in retinal sections. Photoreceptor cell loss and regeneration were assessed by counting recoverin+ (rods) or cone-arrestin+ (cones) photoreceptors and BrdU+ photoreceptor rods and cones. Moreover, retinal morphology and function were evaluated non-invasively in live mice by spectrum-domain optic coherence tomography and electroretinograms.
While A2-/-A3-/- mice exhibited normal retinal morphology as WT mice, both rho-/- and rho-/-A2-/-A3- mice showed significant degeneration of photoreceptor cells and thinning of the outer nuclear layer (ONL). BrdU+ cells were observed in retinal sections of A2-/-A3-/- and rho-/-A2/-A3- mice, but not in those of WT and rho-/- mice. BrdU+recoverin+ cells were observed in the ONL of rho-/-A2-/-A3- mice but not the other tested strains.
Our results suggest that ephrin-A2 and -A3 are key inhibitors for the regenerative potential of retinal progenitor cells and absence of ephrin-A2/A3 promote the proliferation and differentiation of retinal progenitor cells into photoreceptor. Thus, suppression of ephrin-A2/A3 signaling may represent a novel approach of cells-based therapy for photoreceptor degeneration disease.
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