title: Developmental and cellular factors underlying corneal epithelial dysgenesis in the Pax6+/- mouse model of aniridia.
abstract: Heterozygosity for a PAX6 deficiency (PAX6+/-) results in low levels of the PAX6 transcription factor and causes aniridia. Corneal changes in aniridia-related keratopathy (ARK) include peripheral pannus and epithelial abnormalities, which eventually result in corneal opacity and contribute to visual loss. The corneal abnormalities of Pax6+/- mice provide an excellent model for the corneal changes seen in PAX6+/- humans. The aim of the present study was to investigate the contributions of different factors (including altered cell proliferation, abnormal epithelial differentiation and incursion of the conjunctival epithelium) that may underlie the pathogenesis of the corneal changes caused by low levels of Pax6 in heterozygous Pax6+/Sey-Neu (Pax6+/-) mice. BrdU incorporation showed enhanced proliferation of Pax6+/- corneal epithelium compared to wild-type controls and analysis of p63 (a marker of high proliferative potential) revealed a slight increase in frequency of p63-positive basal corneal epithelial cells in Pax6+/- mice. Immunohistochemical investigation of K12 (a Pax6-regulated marker of corneal epithelial differentiation) in 2-52-week-old mice showed that K12 expression was delayed and down-regulated in the Pax6+/- corneal epithelium, implying that differentiation of the Pax6+/- corneal epithelium was delayed and abnormal. Goblet cells were identified within the peripheral corneal epithelium of the Pax6+/- eyes, but some were surrounded by cells expressing K12, suggesting they may have arisen in situ in the corneal epithelium. These findings suggest that low levels of Pax6 may be directly responsible for failure or delay of proper differentiation of the corneal epithelial cells, but the proliferative component of the mutant epithelium is probably not impaired. This abnormal differentiation suggests that ARK is not entirely attributable to a limbal stem cell deficiency.
authors.affiliation: Division of Reproductive and Developmental Sciences, Genes and Development Group, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK.
authors.forename: Thaya
authors.initials: T
authors.lastname: Ramaesh
authors.forename: Kanna
authors.initials: K
authors.lastname: Ramaesh
authors.forename: J
authors.initials: J
authors.lastname: Martin Collinson
authors.forename: Simon A
authors.initials: SA
authors.lastname: Chanas
authors.forename: Baljean
authors.initials: B
authors.lastname: Dhillon
authors.forename: John D
authors.initials: JD
authors.lastname: West
mesh_terms: D000818:Animals; D015783:Aniridia / Q000150:complications* / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation; D049109:Cell Proliferation; D003316:Corneal Diseases / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D019573:Epithelium, Corneal / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D005136:Eye Proteins / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D053551:Keratin-12; D007633:Keratins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008817:Mice, Mutant Strains; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D010750:Phosphoproteins / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; C507495:KRT12 protein, mouse; D053551:Keratin-12; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D010750:Phosphoproteins; D012097:Repressor Proteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D007633:Keratins