Chronic wound state exacerbated by oxidative stress in Pax6+/- aniridia-related keratopathy.
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.
Ou
J
J
School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, UK.
Walczysko
P
P
Kucerova
R
R
Rajnicek
A M
AM
McCaig
C D
CD
Zhao
M
M
Collinson
J M
JM
D000818:Animals; D015783:Aniridia / Q000378:metabolism*; D002908:Chronic Disease; D003316:Corneal Diseases / Q000378:metabolism*; D019573:Epithelium, Corneal / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000032:analysis / Q000378:metabolism; D005136:Eye Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D005978:Glutathione / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008855:Microscopy, Electron, Scanning; D023421:Models, Animal; D018384:Oxidative Stress; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014945:Wound Healing
D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; D006861:Hydrogen Peroxide; D048049:Extracellular Signal-Regulated MAP Kinases; D005978:Glutathione