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

   
Author J Ou, P Walczysko, R Kucerova, A M Rajnicek, C D McCaig, M Zhao, J M Collinson
Citation Information The Journal of pathology, 215:421-30 (2008)
Keywords Animals, Aniridia, Chronic Disease, Corneal Diseases, Epithelium, Corneal, Extracellular Signal-Regulated MAP Kinases, Eye Proteins, Glutathione, Homeodomain Proteins, Hydrogen Peroxide, Mice, Mice, Inbred CBA, Mice, Knockout, Microscopy, Electron, Scanning, Models, Animal, Oxidative Stress, Paired Box Transcription Factors, Repressor Proteins, Signal Transduction, Wound Healing
Species: Mouse
Related Products S7150
Pub Med ID 18491289
   

Abstract

Heterozygosity for the transcription factor PAX6 causes eye disease in humans, characterized by corneal opacity. The molecular aetiology of such disease was investigated using a Pax6+/- 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/myofibroblast 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.