Endothelin-2-Mediated Protection of Mutant Photoreceptors in Inherited Photoreceptor Degeneration

Alexa N. Bramall, Michael J. Szego, Laura R. Pacione, Inik Chang, Eduardo Diez, Pedro D'Orleans-Juste, Duncan J. Stewart, William W. Hauswirth, Masashi Yanagisawa, Roderick R. McInnes

Research output: Contribution to journalArticle

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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 Pde6brd1 alleles or the Tg(RHO P347S) transgene. In the Edn2-/- background, PR survival increased 110% in Pde6brd1/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 Pde6brd1/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 Pde6brd1/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 Pde6brd1/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.

Original languageEnglish (US)
Article numbere58023
JournalPLoS One
Volume8
Issue number2
DOIs
StatePublished - Feb 28 2013

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Endothelin-2
endothelins
photoreceptors
mutants
retina
mice
Retina
Fibroblast Growth Factor 2

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Bramall, A. N., Szego, M. J., Pacione, L. R., Chang, I., Diez, E., D'Orleans-Juste, P., ... McInnes, R. R. (2013). Endothelin-2-Mediated Protection of Mutant Photoreceptors in Inherited Photoreceptor Degeneration. PLoS One, 8(2), [e58023]. https://doi.org/10.1371/journal.pone.0058023

Endothelin-2-Mediated Protection of Mutant Photoreceptors in Inherited Photoreceptor Degeneration. / Bramall, Alexa N.; Szego, Michael J.; Pacione, Laura R.; Chang, Inik; Diez, Eduardo; D'Orleans-Juste, Pedro; Stewart, Duncan J.; Hauswirth, William W.; Yanagisawa, Masashi; McInnes, Roderick R.

In: PLoS One, Vol. 8, No. 2, e58023, 28.02.2013.

Research output: Contribution to journalArticle

Bramall, AN, Szego, MJ, Pacione, LR, Chang, I, Diez, E, D'Orleans-Juste, P, Stewart, DJ, Hauswirth, WW, Yanagisawa, M & McInnes, RR 2013, 'Endothelin-2-Mediated Protection of Mutant Photoreceptors in Inherited Photoreceptor Degeneration', PLoS One, vol. 8, no. 2, e58023. https://doi.org/10.1371/journal.pone.0058023
Bramall AN, Szego MJ, Pacione LR, Chang I, Diez E, D'Orleans-Juste P et al. Endothelin-2-Mediated Protection of Mutant Photoreceptors in Inherited Photoreceptor Degeneration. PLoS One. 2013 Feb 28;8(2). e58023. https://doi.org/10.1371/journal.pone.0058023
Bramall, Alexa N. ; Szego, Michael J. ; Pacione, Laura R. ; Chang, Inik ; Diez, Eduardo ; D'Orleans-Juste, Pedro ; Stewart, Duncan J. ; Hauswirth, William W. ; Yanagisawa, Masashi ; McInnes, Roderick R. / Endothelin-2-Mediated Protection of Mutant Photoreceptors in Inherited Photoreceptor Degeneration. In: PLoS One. 2013 ; Vol. 8, No. 2.
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AU - Diez, Eduardo

AU - D'Orleans-Juste, Pedro

AU - Stewart, Duncan J.

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