Abstract
Purpose: To investigate whether and how leukemia inhibitory factor (Lif) is involved in mediating the neuroprotective effects of Norrin on retinal ganglion cells (RGC) following excitotoxic damage. Norrin is a secreted protein that protects RGC from N-methyl-d-aspartate (NMDA)-mediated excitotoxic damage, which is accompanied by increased expression of protective factors such as Lif, Edn2 and Fgf2. Methods: Lif-deficient mice were injected with NMDA in one eye and NMDA plus Norrin into the other eye. RGC damage was investigated and quantified by TUNEL labeling 24 h after injection. Retinal mRNA expression was analyzed by quantitative real-time polymerase chain reaction following retinal treatment. Results: After intravitreal injection of NMDA and Norrin in wild-type mice approximately 50% less TUNEL positive cells were observed in the RGC layer when compared to NMDA-treated littermates, an effect which was lost in Lif-deficient mice. The mRNA expression for Gfap, a marker for Müller cell gliosis, as well as Edn2 and Fgf2 was induced in wild-type mice following NMDA/Norrin treatment but substantially blocked in Lif-deficient mice. Conclusions: Norrin mediates its protective properties on RGC via Lif, which is required to enhance Müller cell gliosis and to induce protective factors such as Edn2 or Fgf2.
Highlights
Light is perceived by photoreceptors, which transmit their visual information via horizontal, amacrine and bipolar cells for initial neuronal processing to retinal ganglion cells (RGC), which are located in the inner retina
Since Norrin induces the expression of leukemia inhibitory factor (Lif), we investigated whether Norrin mediates its effects on Müller cells and retinal neurons via an induction of Lif as a central downstream signaling molecule
Our conclusions are based upon three central findings: (1) the Norrin-mediated protective effect on acutely damaged retinal neurons is lost in Lif+/− and Lif−/−
Summary
Light is perceived by photoreceptors, which transmit their visual information via horizontal, amacrine and bipolar cells for initial neuronal processing to retinal ganglion cells (RGC), which are located in the inner retina. RGC project their axons to the brain after converging at the optic disc to form the optic nerve [1]. The importance of RGC for visual function is pointed out in diseases such as glaucoma or Leber’s hereditary optic neuropathy leading to degeneration of RGC and subsequent blindness [2]. Is the leading risk factor for disease progression and IOP lowering is the only therapeutic option so far. Despite sufficient IOP regulation, some patients experience a further disease progression, suggesting that additional mechanisms might contribute to glaucomatous RGC degeneration [3].
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