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M.E. Pennesi, S. Yoo, S.M. Wu, H. Zogbhi; SCA7 Knock-In Mice Reproduce the Retinal Degeneration Seen in Human SCA7 . Invest. Ophthalmol. Vis. Sci. 2003;44(13):532.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To characterize the retinal degeneration in a mouse model of Spinocerebellar Ataxia Type 7 (SCA7) Methods: SCA7 knock-in mice were generated by introducing 266 CAG repeats (a number that causes infantile-onset disease in human) into the mouse Sca7 locus by homologous recombination in embryonic stem cell. To examine the alterations in the expression of photoreceptor-specific genes, total RNA was extracted from the retina and assayed using Northern Blots. To test retinal function, full field electroretinograms (ERGs) were measured from wild-type and mutant mice at 5, 9, and 14 weeks. Changes in retinal structure were examined using both light and confocal microscopy. Results: At five weeks, rod-driven ERGs in mutant mice were similar to those measured from control mice. There was a slight decrease in the ERG response from M-cones, but not UV-cones. Expression of rod specific genes in mutant mice at this age was slightly decreased, but expression of both the M- and S-pigment genes were both significantly decreased. At nine weeks, cone-driven ERGs were severely decreased while rod-driven ERGs were moderately decreased. Histology from these mice revealed shortened outer segments, but little cell death. Cone-driven ERGs were absent in 14-week-old mice and rod-driven ERGs were severely reduced. Immunohistochemistry revealed the progressive accumulation of mutant ataxin-7 throughout most cell types in the retina, leading to the formation of nuclear inclusions (NIs); however, NIs appeared after retinal dysfunction in mutant mice. Interestingly, mutant ataxin accumulated faster in cone photoreceptors compared to rods. Conclusion: Our study shows that SCA7 knock-in mice undergo a progressive cone-rod dystrophy as it has been shown in SCA7 patients. Accumulation of mutant ataxin-7 in knock-in mouse retina is correlated with a progressive down-regulation of photoreceptor-specific genes, leading to the structural disorganization of outer segments, and thus to retinal dysfunction. Overall, SCA7 knock-in mice recapitulate the retinal degeneration seen in humans with Spinocerebellar Ataxia Type 7 and can serve as a useful model for studying the disease.
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