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N. Haider, J.K. Naggert, P.M. Nishina; The Transcription Factor NR2E3 Suppresses Cone Cell Proliferation . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3982.
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Purpose: In previous studies, we determined that rd7 mice, harboring a mutation in Nr2e3, have excess blue cone cells. The current study was designed to determine to if rd7 mice have any proliferation defects during retinal development. Methods:The rd7 mouse and littermate controls were used in this study. Localization of NR2E3 was examined at P2 and P21 by immunohistochemistry on whole mount retinas as well as retinal sections. Western blot analysis, immunohistochemistry, and real–time PCR, were performed on B6 and rd7retinas at P2, P14, and P21 using antibodies and primers associated with photoreceptor and müller glial cells. BrdU incorporation was assessed from E10.5 through P21. Apoptosis in rd7 versus wildtype was measured using serial sections at P2, P14, and P21 by TUNEL staining. Results:NR2E3 is expressed in the neuroblastic layers of developing photoreceptor cells at P2 and in the outer nuclear layer of adult photoreceptors. BrdU incorporation studies show that rd7mice undergo prolonged phase of proliferation beyond what is normally detected for wildtype mice. These proliferating cells appear to differentiate into cone photoreceptor cells. The rd7 mice do not exhibit altered expression in the levels of P27, a cell cycle inhibitor that is down regulated during active gliosis. Expression of opsin genes, which are the molecules that identify differentiated photoreceptor cells, indicate rd7 mice have increased blue cone cells with no observable change in rod or green opsins. Furthermore, the extra cone cells do not arise from a decrease in apoptosis during retinal development. Conclusions:Our results suggest that a function of NR2E3 in the developing retina is to suppress cone cell proliferation. rd7 mice lack NR2E3 and exhibit retinal dysplasia due to excess cone photoreceptor cells. These extra blue cells do not appear to arise by compromising either green cones or rods or by perturbation of the apoptotic mechanisms required for proper formation of the mature retina.
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