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C.-Y. Liu, T. Chikama, Y. Hayashi, C. W. C. Kao, L. Wang, J. Meij, T. Nishida, W. W.-. Y. Kao; Age-Dependent Corneal Anomalies by Excess FGF7 in Bitransgenic Krt12-rtTA/tetO-FGF7 Mice Upon Doxycyclin Induction. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4929.
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It has been shown that transgenic mice over-expressing FGF7 (also known as keratinocyte growth factor, KGF) by lens-specific crystalline promoter induced hyperproliferation of embryonic corneal epithelial cells and their subsequent differentiation into lacrimal gland-like tissues. To further investigate the role of this cytokine in corneal morphogenesis during development and homeostasis following development, we used a novel bi-transgenic mice, Krt12-rtTA/tetO-FGF7, to over-express KGF specifically in corneal epithelium by doxycycline (Dox) induction.
Krt12-rtTA/tetO-FGF7 mice were fed Dox to induce FGF7 expression during embryonic (E) development and/or at different postnatal (P) ages. Clinical examinations of mouse eyes were performed by slit lamp and HRT II-cornea module before and after Dox induction. Immunohistochimistry was used to evaluate cell behaviors including growth and differentiation between induced and non-induced animals.
Dox-induced excess FGF7 affected restrictively to the cornea and did not disrupt morphogenesis of surrounding ocular surface tissues of Krt12-rtTA/tetO-FGF7 mice. Induction from E0~P1 caused epithelial cell hypertrophy with both K12 and K14 positive staining in central and peripheral cornea and formation of BrdU+ but K12, K14-negative clonal cells in limbal basal region. Induction from E0~P21 resulted in corneal cloudiness with massive neovascularization and inflammatory cell invasion into both epithelium and stroma. Interestingly, mice at 3-month-old were induced with Dox for 6 weeks, the corneal thickness is doubled in epithelium, but cornea still remained transparent. The reversibility of these corneal epithelial anomalies after removal of Dox from the diet is also age-dependent.
The present study demonstrated that corneal epithelium differentially responses to excess KGF in age-dependent manner. These transgenic mice provide a valuable model system to study the mechanisms underlying cell fate decisions in corneal epithelium morphogenesis during development and homeostasis in adulthood.
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