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Yvon Trottier, Alice Karam, Chantal Weber, Marina G. Yefimova; Muller Glial Cell Proliferation And Generation Of New Photoreceptors During Retinal Degeneration In Spinocerebellar Ataxia 7 Mouse Model. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1362.
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© ARVO (1962-2015); The Authors (2016-present)
Spinocerebellar ataxia 7 (SCA7) is a polyglutamine (polyQ) expansion disease characterized by cerebellar and retinal degeneration. The SCA7 R7E mice display a progressive retinal dysfunction that is due to the loss of rod differentiation phenotype. After one year of disease duration, surviving rods have lost their segments and show no degenerative sign. Interestingly, at early disease stages, a transient apoptotic wave associated with cell proliferation is observed in the outer nuclear layer (ONL). In this study, we analyzed the origin, identity and fate of the proliferating cells to understand their role in the SCA7 retinopathy.
SCA7 and WT littermate mice were injected with bromodeoxyuridine (BrdU) at different post-natal days (PN) ranging from PN12 to PN42 to label proliferating cells. Other mice received a single dose of BrdU at PN14 and were subsequently analyzed from PN14 to PN42 to trace the proliferating cells over time. Mitotic cells were labeled by immunofluorescence with phospho-histone 3 (PH3) antibody, while identity and fate of proliferating cells were studied using retinal cell specific markers and TUNEL staining.
While few BrdU+ cells are detected in WT retina, they are abundant in SCA7 retina from PN12 to 42, with a peak of BrdU+ cell production at PN17. Most BrdU+ cells are located in the inner nuclear layer (INL) at PN12-14, however, they are exclusively located in the ONL from PN21. By tracing the proliferating cells, we show that BrdU+ cells migrate from INL to ONL and express Müller glial cell markers. At PN21, one third of BrdU+cells expresses rod specific markers. These BrdU+/rod+ cells persist for up to 3 weeks in SCA7 retina, whereas the number of BrdU+/rod- cells declines over time.
Our results suggest that in response to polyQ toxicity in SCA7 mouse retina, Müller glia proliferate, migrate in the ONL where they might transdifferentiate into persistent rod photoreceptors. While transdifferentiation of Müller glia to photoreceptors was shown to occur in mammalian retina upon acute injury, our study proposes that this transdifferentiation phenomenon might also be an inherent feature of some retinal degenerative diseases.
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