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The Journal of Neuroscience, December 17, 2008, 28(51):13765-13774; doi:10.1523/JNEUROSCI.5114-08.2008

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Neurobiology of Disease
Leukemia Inhibitory Factor Extends the Lifespan of Injured Photoreceptors In Vivo

Sandrine Joly, Christina Lange, Markus Thiersch, Marijana Samardzija, and Christian Grimm

Laboratory for Retinal Cell Biology, Department of Ophthalmology, Center for Integrative Human Physiology and Neuroscience Center Zurich, University of Zurich, 8091 Zurich, Switzerland

Correspondence should be addressed to Christian Grimm, Laboratory for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Frauenklinikstrasse 24, 8091 Zurich, Switzerland. Email: cgrimm{at}opht.uzh.ch

Survival and death of photoreceptors in degenerative diseases of the retina is controlled by a multitude of genes and endogenous factors. Some genes may be involved in the degenerative process itself whereas others may be part of an endogenous defense system. We show in two models of retinal degeneration that photoreceptor death strongly induces expression of leukemia inhibitory factor (LIF) in a subset of Muller glia cells in the inner nuclear layer of the retina. LIF expression is essential to induce an extensive intraretinal signaling system which includes Muller cells and photoreceptors and is characterized by an upregulation of Edn2, STAT3, FGF2 and GFAP. In the absence of LIF, Muller cells remain quiescent, the signaling system is not activated and retinal degeneration is strongly accelerated. Intravitreal application of recombinant LIF induces the full molecular pathway including the activation of Muller cells in wild-type and Lif–/– mice. Interruption of the signaling cascade by an Edn2 receptor antagonist increases whereas activation of the receptor decreases photoreceptor cell death. Thus, LIF is essential and sufficient to activate an extensive molecular defense response to photoreceptor injury. Our data establish LIF as a Muller cell derived neuronal survival factor which controls an intrinsic protective mechanism that includes Edn2 signaling to support photoreceptor cell survival and to preserve vision in the injured retina.

Key words: leukemia inhibitory factor; Edn2; retina; photoreceptor degeneration; neuroprotection; endogenous rescue pathway

Received Oct. 23, 2008; revised Oct. 31, 2008; accepted Nov. 1, 2008.

Correspondence should be addressed to Christian Grimm, Laboratory for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Frauenklinikstrasse 24, 8091 Zurich, Switzerland. Email: cgrimm{at}opht.uzh.ch


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