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J. D. Ash, Y. Ueki, Y. Z. Le, S. Chollangi; Evidence That Leukemia Inhibitory Factor (LIF) Protects Photoreceptors From Light Damage Independent of Müller Cell Activation. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2067.
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Our previous study has shown that intravitreal injection of a gp130 ligand, leukemia inhibitory factor (LIF), protects photoreceptor function and prevents photoreceptor cell death from light damage by activating STAT3 and/or ERK1/2. The purpose of this study was to determine the effects of a mosaic gp130 knockout on LIF-induced signaling and protection of photoreceptors from light damage.
Human VMD2-cre transgenic mice that have cre activity ectopically in a mosaic pattern of inner retinal cells were mated with gp130flox/flox mice to achieve a mosaic gp130 conditional knockout (Cre+ gp130flox/flox). Cre- littermates were used as a control for all experiments. Cre activity was assessed and localized by PCR analyses and Rosa functional assay. LIF was injected intravitreally into one eye of 6-7 week-old mice, and PBS was injected into the other eye as a control. STAT3 and ERK1/2 activation was quantified and localized by Western blot and IHC. Protection from light damage was assessed by ERG and histology following mosaic deletion of gp130.
gp130 deletion was detected as early as E15 in cre+ retinas. A Mosaic pattern of Cre activity was detected in number of retinal cells including Müller cells. In cre+ retina, there was significant decrease (approximately 50% decrease) in LIF dependent STAT3 and ERK1/2 activation in Müller cells. Activation of STAT3 in other retinal cells was not significantly reduced by Western blots and IHC. ERG and histological evaluation revealed that LIF protected photoreceptors from light damage equally well in both cre- and cre+ retinas.
Our data show that LIF protects photoreceptor function and prevents photoreceptor death even when 50% of Muller cells cannot respond to LIF. This data is consistent with the hypothesis that LIF directly activates gp130 on photoreceptors to induce protection in a cell autonomous mechanism.
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