Chronic wound state exacerbated by oxidative stress in Pax6+/-aniridia-related keratopathy

J. Ou, P. Walczysko, R. Kucerova, A. M. Rajnicek, C. D. McCaig, M. Zhao, J. M. Collinson

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Heterozygosity for the transcription factor PAX 6 causes eye disease in humans, characterized by, corneal opacity. The molecular aetiology of such disease was investigated using a Pax(+/-) mouse model. We found that the barrier function of uninjured Pax6(+/-) corneas was compromised and that Ca2+-PKC/PLC-ERK/p38 signalling pathways were abnormally activated, mimicking a 'wounded' epithelial state. Using proteomic analysis and direct assay for oxidized proteins, Pax6(+/-) corneas were found to be susceptible to oxidative stress and they exhibited a wound-healing delay which could be rescued by, providing reducing agents such as glutathione. Pax6 protein was oxidized and excluded from the nucleus of stressed corneal epithelial cells, with concomitant loss of corneal epithelial markers and expression of fibroblast/myolibroblast markers. We suggest a chronic wound model for Pax6-related corneal diseases, in which oxidative stress underlies a positive feedback mechanism by depleting nuclear Pax6, delaying wound healing, and activating cell signalling pathways that lead to metaplasia of the corneal epithelium. The study mechanistically links a relatively minor dosage deficiency of a transcription factor with potentially catastrophic degenerative corneal disease. Copyright (c) 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Original languageEnglish
Pages (from-to)421-430
Number of pages10
JournalThe Journal of pathology
Volume215
Issue number4
Early online date17 Apr 2008
DOIs
Publication statusPublished - Aug 2008

Keywords

  • aniridia
  • aniridic keratopathy
  • Pax6
  • cornea
  • oxidative stress
  • pharmacology
  • haploinsufficiency
  • metalloproteinase gelatinaseB
  • glutathione-S-transferase
  • activated protein-kinase
  • corneal epithelial-cells
  • aldehyde dehydrogenase
  • intracellular calcium
  • mouse model
  • map kinase
  • PAX6
  • expression

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