title: Expression of leukemia inhibitory factor in Müller glia cells is regulated by a redox-dependent mRNA stability mechanism.
abstract: BACKGROUND
  Photoreceptor degeneration is a main hallmark of many blinding diseases making protection of photoreceptors crucial to prevent vision loss. Thus, regulation of endogenous neuroprotective factors may be key for cell survival and attenuation of disease progression. Important neuroprotective factors in the retina include H2O2 generated by injured photoreceptors, and leukemia inhibitory factor (LIF) expressed in Müller glia cells in response to photoreceptor damage.
  
  
  RESULTS
  We present evidence that H2O2 connects to the LIF response by inducing stabilization of Lif transcripts in Müller cells. This process was independent of active gene transcription and p38 MAPK, but relied on AU-rich elements (AREs), which we identified within the highly conserved Lif 3'UTR. Affinity purification combined with quantitative mass spectrometry identified several proteins that bound to these AREs. Among those, interleukin enhancer binding factor 3 (ILF3) was confirmed to participate in the redox-dependent Lif mRNA stabilization. Additionally we show that KH-type splicing regulatory protein (KHSRP) was crucial for maintaining basal Lif expression levels in non-stressed Müller cells.
  
  
  CONCLUSIONS
  Our results suggest that H2O2-induced redox signaling increases Lif transcript levels through ILF3 mediated mRNA stabilization. Generation of H2O2 by injured photoreceptors may thus enhance stability of Lif mRNA and therefore augment neuroprotective LIF signaling during degenerative conditions in vivo.
authors.affiliation: Department of Ophthalmology, Lab for Retinal Cell Biology, University of Zurich, Wagistrasse 14, Zurich, 8091, Switzerland. cavitagca@gmail.com.|Present address: Department of Biomedicine, University Hospital Basel, Basel, 4031, Switzerland. cavitagca@gmail.com.
authors.forename: Cavit
authors.initials: C
authors.lastname: Agca
authors.affiliation: Division of Experimental Ophthalmology and Medical Proteome Center, Centre for Ophthalmology, University of Tübingen, 72076, Tübingen, Germany. karsten.boldt@uni-tuebingen.de.
authors.forename: Karsten
authors.initials: K
authors.lastname: Boldt
authors.affiliation: Department of Ophthalmology, Lab for Retinal Cell Biology, University of Zurich, Wagistrasse 14, Zurich, 8091, Switzerland. andrea.gubler@usz.ch.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gubler
authors.affiliation: Department of Ophthalmology, Lab for Retinal Cell Biology, University of Zurich, Wagistrasse 14, Zurich, 8091, Switzerland. isabelle.meneau@usz.ch.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Meneau
authors.affiliation: Department of Gynecology, University of Zurich, Zurich, 8091, Switzerland. armelle.corpet@univ-lyon1.fr.|Present address: Center for Molecular and Cellular Physiology and Genetics, University Lyon I, Villeurbanne, France. armelle.corpet@univ-lyon1.fr.
authors.forename: Armelle
authors.initials: A
authors.lastname: Corpet
authors.affiliation: Department of Ophthalmology, Lab for Retinal Cell Biology, University of Zurich, Wagistrasse 14, Zurich, 8091, Switzerland. samam@usz.uzh.ch.
authors.forename: Marijana
authors.initials: M
authors.lastname: Samardzija
authors.affiliation: Department of Gynecology, University of Zurich, Zurich, 8091, Switzerland. manuel.stucki@usz.ch.
authors.forename: Manuel
authors.initials: M
authors.lastname: Stucki
authors.affiliation: Division of Experimental Ophthalmology and Medical Proteome Center, Centre for Ophthalmology, University of Tübingen, 72076, Tübingen, Germany. Marius.Ueffing@uni-tuebingen.de.
authors.forename: Marius
authors.initials: M
authors.lastname: Ueffing
authors.affiliation: Department of Ophthalmology, Lab for Retinal Cell Biology, University of Zurich, Wagistrasse 14, Zurich, 8091, Switzerland. cgrimm@opht.uzh.ch.|Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, 8091, Switzerland. cgrimm@opht.uzh.ch.|Neuroscience Center (ZNZ), University of Zurich, Zurich, 8091, Switzerland. cgrimm@opht.uzh.ch.
authors.forename: Christian
authors.initials: C
authors.lastname: Grimm
mesh_terms: D000818:Animals; D002460:Cell Line; D063928:Ependymoglial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D006861:Hydrogen Peroxide / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000378:metabolism*; D051379:Mice; D010084:Oxidation-Reduction; D020871:RNA Stability / Q000235:genetics*; D051381:Rats; D012160:Retina / Q000378:metabolism*; D012162:Retinal Degeneration / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D053605:Leukemia Inhibitory Factor; D006861:Hydrogen Peroxide