Cyr61 activates retinal cells and prolongs photoreceptor survival in rd1 mouse model of retinitis pigmentosa

• Published in: Journal of neurochemistry 2014-07, Vol.130 (2), p.227-240
• Main Authors: Kucharska, Joanna, del Río, Patricia, Arango‐Gonzalez, Blanca, Gorza, Matteo, Feuchtinger, Annette, Hauck, Stefanie M., Ueffing, Marius
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; Cell Death - drug effects; Cell Separation; Cysteine-Rich Protein 61 - genetics; Cysteine-Rich Protein 61 - pharmacology; Cytokines - metabolism; Eye diseases; Glial Cell Line-Derived Neurotrophic Factor - pharmacology; Humans; Image Processing, Computer-Assisted; In Situ Nick-End Labeling; Kinases; MAP Kinase Signaling System - drug effects; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Neurochemistry; neuroprotection; Organ Culture Techniques; Phosphorylation; Photoreceptor Cells, Vertebrate - drug effects; Photoreceptor Cells, Vertebrate - physiology; Photoreceptors; Primary Cell Culture; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - physiology; Recombinant Proteins - pharmacology; Retina - cytology; Retina - drug effects; retinal degeneration; Retinal Ganglion Cells - drug effects; Retinal Ganglion Cells - physiology; Retinitis Pigmentosa - pathology; RMG; Rodents; RPE; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - physiology; Swine
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12704

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 Pde6brd1 retinas. To identify stimulated pathways in the retina, we treated Pde6brd1 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. 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.