Abstract
Purpose: :
Survival and death of photoreceptors in degenerative diseases of the retina is controlled by a multitude of genes and endogenous factors. Here we analyzed the role of leukemia inhibitory factor (LIF) for cell survival in a model of induced and a model of inherited retinal degeneration.
Methods: :
Retinal morphology was analyzed by light microscopy. Gene expression was studied using real-time PCR, Western blotting, in situ hybridization and immunfluorescence. Recombinant LIF, BQ-788 (Ednrb agonist), BQ-3020 (Ednrb antagonist) were injected intravitreally. For light exposure, wild type and Lif-/- animals were dark adapted over night and exposed to 2 hours of 13’000 lux of white light with dilated pupils. VPP mice - a model for autosomal dominant RP - on a wild type or on a Lif-/- background were sacrificed at different postnatal days for analysis of the retina.
Results: :
Photoreceptor injury induced expression of LIF in a subset of Muller glia cells. Increased expression of LIF was essential to induce gene expression of Edn2, STAT3, GFAP and FGF2 and to phosphorylate transcription factor STAT3. Lack of LIF prevented the activation of this signaling cascade and increased photoreceptor degeneration in the light damaged as well as in the VPP retina. Injection of rLIF or of an Ednrb agonist was sufficient to activate the molecular response in wild type mice. Application of an Ednrb antagonist increased photoreceptor loss in the VPP retina whereas application of an Ednrb agonist was protective.
Conclusions: :
Photoreceptor injury is ‘sensed’ by a subset of Muller glia cells which induce a LIF-controlled elaborate rescue pathway including STAT3 phosphorylation, Edn2 signaling, activation of GFAP and expression of the growth and survival factor FGF2. Absence of LIF results in only basal expression of these factors, even in the presence of photoreceptor damage. Lack of FGF2 induction may be the main reason for the acceleration of disease progression in the absence of LIF. This suggests that LIF may be a key factor for an endogenous response of the retina aiming at the protection of cells and preservation of function.
Keywords: retinal degenerations: cell biology • neuroprotection • cell survival