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Targeted Deletion of AP-2 Leads to Disruption in Corneal Epithelial Cell Integrity and Defects in the Corneal Stroma

¹From the Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; ²Human Genetics and Molecular Medicine, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel; and the ³Departments of Craniofacial Biology and Cell and Developmental Biology, University of Colorado Health Sciences Center, Denver, Colorado.

PURPOSE. The present study was undertaken to create a conditional knockout of AP-2 in the corneal epithelium.

METHODS. A line of mice expressing Cre-recombinase specifically in the early lens placode was crossed with mice in which the AP-2 allele is flanked by two loxP sites. The resultant Le-AP-2 mutants exhibited a targeted deletion of AP-2 in lens placode derivatives, including the differentiating corneal epithelium.

RESULTS. The Le-AP-2 mutant mice were viable and had a normal lifespan. The adult corneal epithelium exhibited a variation in the number of stratified epithelial layers, ranging from 2 to 10 cell layers. A substantial decrease in expression of the cell–cell adhesion molecule, E-cadherin, was observed in all layers of the Le-AP-2 mutant corneal epithelium. The basement membrane, or Bowman’s layer, was thinner in the mutant cornea and in many regions was discontinuous. These defects corresponded with altered distribution of laminin and entactin, and to a lesser degree, type IV collagen. The Le-AP-2 mutant cornea also exhibited stromal defects, including disrupted organization of the collagen lamellae and accumulation of fibroblasts beneath the epithelium that showed increased immunoreactivity for proliferating cell nuclear antigen (PCNA), -smooth muscle actin (-SMA), p-Smad2, and TGF-ß2.

CONCLUSIONS. In the absence of AP-2, the corneal epithelium exhibits altered cell adhesion and integrity and defects in its underlying basement membrane. These defects likely caused the alterations in the corneal stroma.

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