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A. Husson–Danan, T. Leveillard, S. Mohand–Said, F. Chalmel, O. Poch, J.–A. Sahel; Rod–Derived Cone Viability Factor/Txnl–6 Expression in the Transgenic P23H Rat, an Autosomal Dominant Model of Retinitis Pigmentosa . Invest. Ophthalmol. Vis. Sci. 2005;46(13):5185.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Rod–derived Cone Viability Factor/Txnl–6 (RdCVF) a trophic factor secreted by rods and required for cone rescue is a clue for therapy of retinitis pigmentosa. It has been demonstrated that in a mouse model of human recessive retinitis pigmentosa, the rd1 mouse, RdCVF prevent secondary cone degeneration. This activity is theoretically independent of the primary genetic lesion affecting rod photoreceptors. To confirm the validity of this new therapeutic strategy, we have studied RdCVF expression in the transgenic P23H rat, that carries the dominant mutation in the rhodopsin gene most commonly found in humans. Methods: By mining genomic databases, we have identified rat RdCVF sequence. RdCVF expression was studied on retinal extracts from transgenic P23H and S334–ter rats and compared to wild–type rats using real–time PCR and western–blotting. We performed stereological counting to estimate the total cone numbers on flat mounted retinas and immunohistochemistry on retinal sections to localize RdCVF in retinal layers. Results: RdCVF mRNA from rat retina has been sequenced and two distinct mRNAs encoding a short and a long form of the RdCVF polypeptides have been identified, with a predominant expression for the short one. Using real–time PCR, we report a large decrease in RdCVF mRNA expression for the both transgenic animal models for advanced stages of rod degeneration at 43 weeks (w43). Regarding protein expression, we have noticed a progressive and slow diminution with the age between post–natal day 10 (PN10) and w18 by western blotting. A correlation between RdCVF and rod degeneration was observed by immunohistochemistry, the staining in rod–outer segments decreasing as rod degenerate between PN10 days and w15. The progressive cone loss was documented by stereological counting. For the P23H rat, we have noticed a loss of 16% of the cone population between w30 and w12, and for S334–ter rats, a loss of 23% of their cones between w8 and w17. Conclusions: These results confirm the hypothesis linking cone degeneration to rod loss in retinitis pigmentosa, RdCVF being a major factor implicated. Validation of correlation between RdCVF expression and rod degeneration in another animal model represents a hope to generalize the concept to many mutations and many species.
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