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X.–J. Yang, K.D. Rhee, M.M. LaVail, W.W. Hauswirth, D. Bok; Mechanisms of CNTF–Mediated Neural Protection in the P216L rds Transgenic Mouse . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4827.
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© ARVO (1962-2015); The Authors (2016-present)
Ciliary neurotrophic factor (CNTF) exhibits neural protective effects in a broad range of retinal disease and injury models. Retinal degeneration slow +/– P216L 1300 (rds) transgenic mice treated with a recombinant adeno–associated virus (rAAV) expressing a secreted CNTF show slowing of photoreceptor loss, but a suppressed ERG and altered photoreceptor nuclear morphology. In this study, we examine the mechanisms of CNTF induced molecular and cellular changes in these mice.
The rds +/– P216L 1300 transgenic mice were injected subretinally with rAAV–CNTF unilaterally between postnatal day 23–25. Injected eyes were examined by ERG prior to harvesting to assess retinal function. Non–injected contralateral and rAAV–CNTF injected eyes were harvested at 30, 72, and 90 days postinjection and processed for immunocytochemistry. In addition, rds mice were injected intravitreally with a single dose of rCNTF followed by BrdU labeling to test for cell proliferation.
Retinas exposed to chronic expression of CNTF showed increased activation of cytokine signaling, as indicated by phospho–ERK and phospho–STAT3 staining. Analyses of retinal cell type markers demonstrated that in the outer nuclear layer (ONL) of rAAV–CNTF treated retina, the majority of cells expressed rhodopsin, thus maintaining rod photoreceptor features, whereas expression of both S–cone and M–cone opsins were decreased. In addition, CNTF treatment increased both the number of cells expressing Müller glial markers and the dispersion of these cells within the inner nuclear layer (INL). Moreover, rAAV–CNTF treatment resulted in an increase and dispersion of Chx10 positive cells in the INL.
CNTF expression mediated by rAAV in the rds +/– P216L 1300 transgenic mouse resulted in preservation of ONL cells with rod photoreceptor features and a significant alteration of INL cells including Müller glia and bipolar cells.
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