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J. T. A. Meij, C. Y. Liu, Y. Zhang, C. W. C. Kao, W. W. Y. Kao; Time-Course of Corneal Stromal Neovascularization and Ocular Surface Squamous Neoplasia Development in Bi-Transgenic Krt12-rtTA/TetO-FGF7 Mice, Depends on Age of Induction. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2368. doi: https://doi.org/.
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Previously, we generated Krt12-rtTA/tetO-FGF7 mice that overexpress FGF7 (KGF) in the corneal epithelium after doxycycline (Dox) treatment, and showed that 1 mo induction in the adult results in reversible epithelial hyperplasia, whereas induction throughout embryonic development causes severe corneal anomalies resembling ocular surface squamous neoplasia (OSSN) (Chikama et al., in press). To further investigate the role of this cytokine in corneal development and homeostasis, a wide range of embryonic (E) and postnatal (P) starting ages and periods of induction were applied.
Krt12-rtTA/tetO-FGF7 dams were treated with 80 µg/g Dox ip, followed by Dox chow for different periods of time. Mouse eyes were examined by in vivo confocal microscopy (HRT II-cornea module) and stereomicroscope. Immunohistochemistry and Western blotting were used to examine protein expression.
(i) Embryonic induction up to only E16.5 caused no surface anomalies at eye-opening, but blood vessels were present in the anterior stroma and persisted for at least 5 mo. Re-induction of these adult mice, led to OSSN within 1 mo. (ii) Dox continued up to E19.5, resulted in an OSSN-like phenotype that did not fully reverse even after 2 mo (iii) Postnatal induction for a period of 2 mo starting within 7 d after birth caused OSSN, but when started at P10 led to corneal hyperplasia and neovascularization, and at P15 or later, to hyperplasia only. (iv) After long-term (4 mo) Dox, also in adult Krt12-rtTA/tetO-FGF7 mice, corneal neovascularization and OSSN ensued.
During embryonic and postnatal development of Krt12-rtTA/tetO-FGF7 mice, there is a period of high susceptibility to FGF7-induced neovascularization and OSSN-like phenotype. This susceptibility decreases with maturation of the cornea. Postnatally, OSSN is preceded by hyperplasia and neovascularization.
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