July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Evidence that Stat3 protects photoreceptors by increasing expression of protein editing genes and decreasing outer segment genes
Author Affiliations & Notes
  • Casey Keuthan
    Ophthalmology, University of Florida, Gainesville, Florida, United States
  • Clayton Santiago
    Ophthalmology, University of Florida, Gainesville, Florida, United States
  • Marcus Hooper
    Ophthalmology, University of Florida, Gainesville, Florida, United States
  • Linda Qian
    Ophthalmology, University of Florida, Gainesville, Florida, United States
  • John D Ash
    Ophthalmology, University of Florida, Gainesville, Florida, United States
  • Footnotes
    Commercial Relationships   Casey Keuthan, None; Clayton Santiago, None; Marcus Hooper, None; Linda Qian, None; John Ash, None
  • Footnotes
    Support  Funding support to JDA includes NIH R01EY016459-12, Foundation Fighting Blindness, and an unrestricted departmental grant from Research to Prevent Blindness, Inc. Training support to CJK includes NIH T32EY007132.
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 4449. doi:
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    • Get Citation

      Casey Keuthan, Clayton Santiago, Marcus Hooper, Linda Qian, John D Ash; Evidence that Stat3 protects photoreceptors by increasing expression of protein editing genes and decreasing outer segment genes. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4449.

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

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Abstract

Purpose : A central hypothesis for neurodegeneration is that cells die when damaged protein load exceeds cellular capacity for clearance. Stat3 has been reported to be a potent neuroprotective factor in photoreceptors, but the mechanisms are poorly understood. In this study, we aimed to elucidate the specific role of Stat3 in regulating either protein load or clearance capacity.

Methods : Chx10Cre;Stat3f/f mice were used as conditional retinal knockouts of Stat3 (Stat3 cKO). Optical Coherence Tomography (OCT) and electroretinography (ERG) were used to measure retinal thickness and function, respectively. Mice were maintained in dim lighting (<50lux), or exposed to 400lux cyclic light for 6 days. To activate Stat3, 2μg/μl of recombinant human leukemia inhibitory factor (LIF) was intravitreally injected into Balb/c mice 2 days prior to collecting retinas for chromatin immunoprecipitation array (ChIP-chip) using an antibody against Y705 p-Stat3. GEO dataset (GSE37773) was included for meta-analysis using pipelines in Galaxy (usegalaxy.org).

Results : Dim-reared Stat3 cKO mice and wild-type mice had normal retinas. Wild-type mice exposed to 400lux of light were under sufficient stress to activate Stat3, but the light did not kill photoreceptors. Surprisingly, Stat3 cKO mice had decreased retinal thickness and a reduction in a-waves after 400lux exposure. Data from ChIP-chip analysis revealed Stat3 binding at 2496 sites in the genome, which potentially control 3597 genes. Meta-analysis of Stat3-bound and light-regulated genes revealed 1537 upregulated and 1768 downregulated genes, representing 92% of Stat3-bound genes. A large cluster of upregulated genes involved processes for proteostasis and regulation of translation. Downregulated processes included phototranduction and ciliary organization genes.

Conclusions : Data show that Stat3 plays an essential role in photoreceptor survival, since Stat3-deficient retinas were sensitive to degeneration by typically non-damaging light. Data from ChIP-chip and gene expression analysis suggests that protection is mediated by multiple mechanisms, including increased protein processing and decreased expression of highly-expressed outer segment genes. The results suggest that Stat3 has a dual role in preventing neurodegeneration by both decreasing load and increasing capacity of proteins that are potentially damaged by stress.

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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