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Masayuki Ohnaka, Katsuaki Miki, Yuan-Yuan Gong, Rebecca Stevens, Takeshi Iwase, Sean F. Hackett, Peter A. Campochiaro; Transgenic Expression of Glial Cell Line-Derived Neurotrophic Factor in Photoreceptor or RPE Delays but Does Not Prevent Photoreceptor Cell Death in rd10 Mice. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6441.
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© ARVO (1962-2015); The Authors (2016-present)
Glial cell line-derived neurotrophic factor (GDNF) is a secreted factor that has been shown to promote survival of photoreceptors. We tested the effect of high expression of GDNF in photoreceptors or RPE in rd10 mice.
Mice that carry the rd10 mutation and have doxycycline (Dox)-inducible expression of GDNF in photoreceptors, IRBP/rtTA-TRE/GDNF-rd10 (IRBP/GDNF/rd10), or RPE, VMD2/rtTA-TRE/GDNF-rd10 (VMD2/GDNF/rd10) were generated. The level of Gdnf mRNA in the eye was measured at P35, P50, and P70. Rod photoreceptor survival was assessed by measuring outer nuclear layer (ONL) thickness, cone photoreceptor survival was assessed by measuring cone density on peanut agglutinin stained retinal whole mounts, and retinal function was assessed by electroretinograms (ERGs).
The level of Gdnf mRNA was 200-fold higher in eyes of Dox-treated IRBP/GDNF/rd10 mice compared to Dox-treated VMD2/GDNF/rd10 mice at P35 and although there was a significant drop at P50 and P70, levels were still more than 10-fold higher in IRBP/GDNF/rd10 mice. Despite the lower GDNF expression, VMD2/GDNF/rd10 mice had significantly thicker ONL than rd10 mice at 6/6 measurement locations, while IRBP/GDNF/rd10 mice had thicker ONL than rd10 mice at 3/6 locations. Compared to rd10 mice, VMD2/GDNF/rd10 and IRBP/GDNF/rd10 mice had significantly greater mean scotopic and photopic b-wave amplitudes at P35, P50, P60, and P70 and not different from each other, except mean photopic b-wave at P35 which was greater for VMD2/GDNF/rd10 mice compared to IRBP/GDNF/rd10 mice. Cone density was significantly greater in VMD2/GDNF/rd10 and IRBP/GDNF/rd10 mice compared to rd10 mice at P50, but by P70 it had decreased substantially in both.
High expression of GDNF in RPE cells or very high expression of GDNF in photoreceptors of rd10 mice promoted temporary survival of rods and cones and preservation of their ERG function. It appears that regardless of the site or level of expression, GDNF can delay, but not prevent photoreceptor cell death in rd10 mice.
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