title: Endothelin-2-mediated protection of mutant photoreceptors in inherited photoreceptor degeneration.
abstract: Expression of the Endothelin-2 (Edn2) mRNA is greatly increased in the photoreceptors (PRs) of mouse models of inherited PR degeneration (IPD). To examine the role of Edn2 in mutant PR survival, we generated Edn2(-/-) mice carrying homozygous Pde6b(rd1) alleles or the Tg(RHO P347S) transgene. In the Edn2(-/-) background, PR survival increased 110% in Pde6b(rd1/rd1) mice at post-natal (PN) day 15, and 60% in Tg(RHO P347S) mice at PN40. In contrast, PR survival was not increased in retinal explants of Pde6b(rd1/rd1) ; Edn2(-/-) mice. This finding, together with systemic abnormalities in Edn2(-/-) mice, suggested that the increased survival of mutant PRs in the Edn2(-/-) background resulted at least partly from the systemic EDN2 loss of function. To examine directly the role of EDN2 in mutant PRs, we used a scAAV5-Edn2 cDNA vector to restore Edn2 expression in Pde6b(rd1/rd1) ; Edn2(-/-) PRs and observed an 18% increase in PR survival at PN14. Importantly, PR survival was also increased after injection of scAAV5-Edn2 into Pde6b(rd1/rd1) retinas, by 31% at PN15. Together, these findings suggest that increased Edn2 expression is protective to mutant PRs. To begin to elucidate Edn2-mediated mechanisms that contribute to PR survival, we used microarray analysis and identified a cohort of 20 genes with >4-fold increased expression in Tg(RHO P347S) retinas, including Fgf2. Notably, increased expression of the FGF2 protein in Tg(RHO P347S) PRs was ablated in Tg(RHO P347S); Edn2(-/-) retinas. Our findings indicate that the increased expression of PR Edn2 increases PR survival, and suggest that the Edn2-dependent increase in PR expression of FGF2 may contribute to the augmented survival.
authors.affiliation: Program in Developmental Biology, The Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Alexa N
authors.initials: AN
authors.lastname: Bramall
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Szego
authors.forename: Laura R
authors.initials: LR
authors.lastname: Pacione
authors.forename: Inik
authors.initials: I
authors.lastname: Chang
authors.forename: Eduardo
authors.initials: E
authors.lastname: Diez
authors.forename: Pedro
authors.initials: P
authors.lastname: D'Orleans-Juste
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Stewart
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
authors.forename: Roderick R
authors.initials: RR
authors.lastname: McInnes
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000378:metabolism; D019333:Endothelin-2 / Q000235:genetics / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000378:metabolism / Q000473:pathology; D012164:Retinal Diseases / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D012243:Rhodopsin / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D019333:Endothelin-2; D012333:RNA, Messenger; D016222:Fibroblast Growth Factor 2; D012243:Rhodopsin; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517438:Pde6b protein, mouse