Norrin Protects Retinal Ganglion Cells from Excitotoxic Damage via the Induction of Leukemia Inhibitory Factor

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.

Neuroprotective Factors of the Retina and Their Role in Promoting Survival of Retinal Ganglion Cells: A Review

“…Another proposed mechanism of neuroprotection involves the leukemia inhibitory factor (LIF), which is necessary for the gliosis of Müller cells -a reaction of neural cells that contributes to the maintenance of retinal homeostasis in physiological and pathological states [104]. After excitotoxic damage, Norrin induces LIF expression in retinal neurons, which in turn stimulates Müller cells to secrete protective factors -endothelin 2 (ET-2) and fibroblast growth factor 2 (FGF2) [105].…”

RNA-Seq Analysis Reveals an Essential Role of the cGMP-PKG-MAPK Pathways in Retinal Degeneration Caused by Cep250 Deficiency

“…In the rd10 mouse retina, an RP mouse model, protective genes such as LIF, fgf2, and edn2 are also extensively upregulated [27]. Norrin, a secreted protein that protects retinal ganglion cells (RGCs) via LIF, is required to enhance Müller cell gliosis and induce protective factors such as Gfap, Edn2, and Fgf2 [28]. Such data lead to the hypothesis that fgf2 and edn2 are protective genes in Cep250 KO mice retina.…”

Molecular Biology of Retinal Ganglion Cells

“…Norrin has also been known for its neuroprotective effects on RGCs following N-methyl-d-aspartate (NMDA)-mediated excitotoxic damage. The article in this issue by Kassumeh and colleagues [ 6 ] examines how leukemia inhibitory factor (Lif) is involved in this protective effect. The authors found that Müller cell gliosis, as well as endothelin 2 (Edn2) and fibroblast growth factor 2 (Fgf2) expression, was substantially blocked in Lif-deficient mice, indicating that Norrin exerts its protective effects through a Lif-dependent manner.…”