July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Genetic Ablation of Cytokine Signaling Inhibitor SOCS3 Promotes Photoreceptor Survival in Mouse Models of Retinitis Pigmentosa
Author Affiliations & Notes
  • Yanjie Wang
    Stein Eye Institute, University of California, Los Angeles, California, United States
  • Kun-Do Rhee
    Stein Eye Institute, University of California, Los Angeles, California, United States
  • Steven Nusinowitz
    Stein Eye Institute, University of California, Los Angeles, California, United States
  • Dean Bok
    Stein Eye Institute, University of California, Los Angeles, California, United States
  • Xian-Jie Yang
    Stein Eye Institute, University of California, Los Angeles, California, United States
  • Footnotes
    Commercial Relationships   Yanjie Wang, None; Kun-Do Rhee, None; Steven Nusinowitz, None; Dean Bok, None; Xian-Jie Yang, None
  • Footnotes
    Support  NIH EY026319
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 3943. doi:
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      Yanjie Wang, Kun-Do Rhee, Steven Nusinowitz, Dean Bok, Xian-Jie Yang; Genetic Ablation of Cytokine Signaling Inhibitor SOCS3 Promotes Photoreceptor Survival in Mouse Models of Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3943.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Suppressor of cytokine signaling 3(SOCS3) is an inhibitor of the JAK-STAT signaling pathway, which is usually activated by growth factors including the neurocytokine ciliary neurotrophic factor (CNTF). We have shown previously in a Peripherin2/rds mouse model that CNTF triggers JAK-STAT3 and ERK activation and prolongs photoreceptor survival. Since SOCS3 expression was significantly elevated following CNTF treatments, in this study we aim to investigate the function of SOCS3 in photoreceptor survival under degeneration conditions in order to provide insight for retinal disease treatment.

Methods : Mice carrying a SOCS3 conditional allele were crossed with two mouse models of retinitis pigmentosa, peripherin2/rds(P216L) and Pde6b/rd10. The Rho-iCre mouse line was used to ablate SOCS3 in rod photoreceptors. Histology, immunocytochemistry, Western blot, realtime RT-PCR and ERG analyses of SOCS3 rodknockout (KO) mutant and control mice were performed.

Results : In both peripherin2/rds(P216L) and Pde6b/rd10 mice, rod-specific SOCS3 deletions resulted in increased thickness of the outernuclear layer. Histological analyses also show improved morphology of the inner and outer segments. In the rds and rd10 retinas, low levels of sporadic STAT3 and ERK activation were observed, mostly in the inner nuclear layer of the degenerating retinas. In SOCS3 rod KOmutants, intensephospho-STAT3 signals were present in rod photoreceptors without exogenous ligand treatment. Western-Blot analysis also detected increased phosphor-STAT3 activation in the SOCS3 rod KO retinas. Furthermore, abroad distribution of phospho-STAT3 and phospho-ERK was observed in the inner retina, suggesting intercellular signaling events between photoreceptor cells and Müller glia. Consistently, Müller glial cell dispersion was enhanced in SOCS3 rod KOmutant mice. Despite structural improvements, ERG showed no difference between SOCS3 rod KO and control mice.

Conclusions : Clinical trials involving secreted CNTF are ongoing for retinitis pigmentosa, dry aged-related macular degeneration, and glaucoma. Our data show that endogenous SOCS3 suppresses photoreceptor to Müller glia signaling under degeneration conditions, and ablation of SOCS3 in rod photoreceptorsis sufficient to result in neuroprotection in mouse models of retinitis pigmentosa. These results thuspointing to new therapeutic strategies.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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