Corneal abnormalities in Pax6+/- small eye mice mimic human aniridia-related keratopathy.
OBJECTIVE
To investigate corneal abnormalities in heterozygous Pax6(+/Sey-Neu) (Pax6(+/-), small eye) mice and compare them with aniridia-related keratopathy in PAX6(+/-) patients.


METHODS
Fetal and postnatal corneal histopathology, adult corneal thickness, and the distribution of K12-immunostained cells were compared in wild-type and Pax6(+/-) mice.


RESULTS
Prenatally, the corneal epithelium was thinner in Pax6(+/-) fetuses than wild-type littermates, but the stroma appeared irregular, hypercellular, and thickened. The anterior chamber angle was obliterated, and the iris was hypoplastic from early developmental stages. The adult Pax6(+/-) corneal epithelium was thinner, had fewer layers, and included goblet cells, indicating repopulation from conjunctival epithelium. The ocular surface was often roughened, with epithelial vacuolation and lens tissue within the stroma. The corneal stroma was thicker centrally, with an irregular lamellar alignment. Many adult Pax6(+/-) corneas were vascularized or contained cellular infiltrates, but some remained clear. Corneal degeneration was age-related: Older Pax6(+/-) mice had prominent subepithelial pannus and more goblet cells in the peripheral corneal epithelium. Cytokeratin 12 stained very weakly in the peripheral and superficial corneal epithelium in 12-month-old Pax6(+/-) mice.


CONCLUSIONS
Corneal abnormalities in Pax6(+/-) mice are similar to those in aniridia-related keratopathy in PAX6(+/-) patients. This extends the relevance of this mouse model of human aniridia to include corneal abnormalities. Incursion of goblet cells suggests impaired function of Pax6(+/-) limbal stem cells, abnormal expression of cytokeratin 12 may result in greater epithelial fragility, and corneal opacities in older mice may reflect poor wound-healing responses to accumulated environmental insults.
Ramaesh
Thaya
T
Department of Reproductive and Developmental Sciences, Genes and Development Group, Princess Alexandra Eye Pavilion, Royal Infirmary of Edinburgh, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
Collinson
J Martin
JM
Ramaesh
Kanna
K
Kaufman
Matthew H
MH
West
John D
JD
Dhillon
Baljean
B
D000818:Animals; D015783:Aniridia / Q000150:complications* / Q000473:pathology; D000869:Anterior Eye Segment; D003315:Cornea / Q000002:abnormalities* / Q000196:embryology / Q000378:metabolism; D003316:Corneal Diseases / Q000209:etiology* / Q000473:pathology; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000502:physiology*; D005260:Female; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D007633:Keratins / Q000378:metabolism; D008297:Male; D051379:Mice; D008850:Microphthalmos / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins
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; D007633:Keratins