title: Cyr61 activates retinal cells and prolongs photoreceptor survival in rd1 mouse model of retinitis pigmentosa.
abstract: Subretinal injections with glial cell line-derived neurotrophic factor (GDNF) rescue morphology as well as function of rod cells in mouse and rat animal models of retinitis pigmentosa. At the same time, it is postulated that this effect is indirect, mediated by activation of retinal Müller glial (RMG) cells. Here, we show that Cyr61/CCN1, one of the secreted proteins up-regulated in primary RMG after glial cell line-derived neurotrophic factor stimulation, provides neuroprotective and pro-survival capacities: Recombinant Cyr61 significantly reduced photoreceptor (PR) cells death in organotypic cultures of Pde6b(rd1) retinas. To identify stimulated pathways in the retina, we treated Pde6b(rd1) retinal explants with Cyr61 and observed an overall increase in activated Erk1/2 and Stat3 signalling molecules characterized by activation-site-specific phosphorylation. To identify Cyr61 retinal target cells, we isolated primary porcine PR, RMG and retinal pigment epithelium (RPE) cells and exposed them separately to Cyr61. Here, RMG as well as RPE cells responded with induced phosphorylation of Erk1/2, Stat3 and Akt. In PR, no increase in phosphorylation in any of the studied proteins was detected, suggesting an indirect neuroprotective effect of Cyr61. Cyr61 may thus act as an endogenous pro-survival factor for PR, contributing to the complex repertoire of neuroprotective activities generated by RMG and RPE cells. We propose the following model of Cyr61 neuroprotection within the retina: Cyr61 stimulates retinal Müller glial (RMG) and retinal pigment epithelium (RPE) cells and activates PI3K/Akt, mitogen-activated protein kinase(MAPK)/Erk and Janus kinase(JAK)/Stat-signalling pathways in these cells. Phosphorylated Stat3 and Erk1/2 presumably translocate to the nucleus, induce transcriptional changes, which increase secretion of neuroprotective agents that protect photoreceptors (PR) from mutation-induced death.
authors.affiliation: Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany; Research Unit Protein Science, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Joanna
authors.initials: J
authors.lastname: Kucharska
authors.forename: Patricia
authors.initials: P
authors.lastname: Del Río
authors.forename: Blanca
authors.initials: B
authors.lastname: Arango-Gonzalez
authors.forename: Matteo
authors.initials: M
authors.lastname: Gorza
authors.forename: Annette
authors.initials: A
authors.lastname: Feuchtinger
authors.forename: Stefanie M
authors.initials: SM
authors.lastname: Hauck
authors.forename: Marius
authors.initials: M
authors.lastname: Ueffing
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D002469:Cell Separation; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D020287:In Situ Nick-End Labeling; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects / Q000502:physiology*; D061251:Primary Cell Culture; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D012160:Retina / Q000166:cytology* / Q000187:drug effects; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000502:physiology; D012174:Retinitis Pigmentosa / Q000473:pathology*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000502:physiology; D013552:Swine
chemical_list: C491850:CCN1 protein, mouse; D055515:Cysteine-Rich Protein 61; D016207:Cytokines; D051100:Glial Cell Line-Derived Neurotrophic Factor; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
keywords: RMG; RPE; neuroprotection; retinal degeneration