title: STAT3 promotes survival of mutant photoreceptors in inherited photoreceptor degeneration models.
abstract: Inherited photoreceptor degenerations (IPDs), a group of incurable progressive blinding diseases, are caused by mutations in more than 200 genes, but little is known about the molecular pathogenesis of photoreceptor (PR) death. Increased retinal expression of STAT3 has been observed in response to many retinal insults, including IPDs, but the role of this increase in PR death is unknown. Here, we show that the expression of Stat3 is increased in PRs of the Tg(RHO P347S) and Prph2(rds) (/+) mouse models of IPD and is activated by tyrosine phosphorylation. PR-specific deletion of Stat3 substantially accelerated PR degeneration in both mutant strains. In contrast, increased PR-specific expression of ROSA26 (R26) alleles encoding either WT STAT3 (Stat3(wt)) or the gain-of-function variant STAT3(C) (Stat3(C)) improved PR survival in both models. Moreover, PR signaling in Tg(RHO P347S) mice carrying either a R26-Stat3(wt) or R26-Stat3(C) allele demonstrated increased a-wave amplitude of the scotopic electroretinogram. Phosphorylation of STAT3 at tyrosine 705 was required for the prosurvival effect because an R26-Stat3(Y705F) allele was not protective. The prosurvival role of enhanced Stat3 activity was validated using recombinant adenoassociated virus (rAAV) vector-mediated PR Stat3 expression in Tg(RHO P347S) mice. Our findings (i) establish that the increase in endogenous PR Stat3 expression is a protective response in IPDs, (ii) suggest that therapeutic augmentation of PR Stat3 expression has potential as a common neuroprotective therapy for these disorders, and (iii) indicate that prosurvival molecules whose expression is increased in mutant PRs may have promise as novel therapies for IPDs.
authors.affiliation: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 1X8; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 1A8;
authors.forename: Ke
authors.initials: K
authors.lastname: Jiang
authors.affiliation: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 1X8; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 1A8;
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Wright
authors.affiliation: Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, FL 32610; and.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhu
authors.affiliation: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 1X8; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 1A8;
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Szego
authors.affiliation: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 1X8; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 1A8;
authors.forename: Alexa N
authors.initials: AN
authors.lastname: Bramall
authors.affiliation: Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, FL 32610; and.
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
authors.affiliation: Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, FL 32610; and.
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Li
authors.affiliation: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 1X8; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 1A8; segan@sickkids.ca rod.mcinnes@mcgill.ca.
authors.forename: Sean E
authors.initials: SE
authors.lastname: Egan
authors.affiliation: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 1X8; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 1A8; Department of Human Genetics and Biochemistry, McGill University and Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada H3T 1E2 segan@sickkids.ca rod.mcinnes@mcgill.ca.
authors.forename: Roderick R
authors.initials: RR
authors.lastname: McInnes
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism* / Q000473:pathology; D022661:RNA, Untranslated / Q000096:biosynthesis / Q000235:genetics; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D022661:RNA, Untranslated; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse
keywords: Stat3; inherited photoreceptor degeneration; neuroprotection