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Winston W. Kao, Jeffrey Miller, Hongshan Liu, William D. Hardie, Chia-Yang Liu; Distinct Pathogenesis by Excess TGF-α: Anterior Segment Dysgenesis (ASD) and FGF-7: Ocular Surface Squamous Neoplasia (OSSN). Invest. Ophthalmol. Vis. Sci. 2011;52(14):309.
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The anterior segment of the vertebrate eye is consisted of cells derived from surface ectoderm and peri-ocular mesenchymal cells of neural crest origin. Morphogenesis of the anterior segments is governed by mutual signaling of growth factors and cytokine between epithelial and mesenchymal cells during embryonic development and homeostasis in adult. In present studies, we compared pathogenesis caused by excess TGF-α to that by excess FGF-7.
A tet-ON binary transgenic Krt12rtTA/tetO-TGF-α mouse line is generated by the cross breeding Krt12-rtTA knock-in mice and tet-O-TGF-α transgenic mice. The binary transgenic mice were subjected to doxycycline induction to over express TGF-α by corneal epithelium. The enucleated eyes of the experimental mice were analyzed by histology, immunohistochemistry. The pathology caused by excess TGF-α was compared to that of excess FGF-7 (our previous studies Am. J. Pathol. 172(3): 638-49. 2008.
Induction of excess TGF-α during or following development resulted in fibrosis and angiogenesis; leading to corneal opacification. Histological examinations revealed that induction of TGF-α initially causes corneal epithelial hyperplasia. As the mouse develops, degeneration of the corneal epithelium occurs, which is accompanied with profound inflammation and neovascularization. In addition, the cornea and iris, which normally form an opened angle, adhere to each other, compromising the formation of the irido-corneal angle, resulting in the loss of the anterior chamber. In comparison, excess FGF-7 caused OSSN due to accumulation and nuclear translocation of β-catenin.
Our data suggests that the levels of biologically active TGF-α in the aqueous humor must be under tight control to maintain proper corneal morphogenesis and homeostasis. This proper spatial development is required to prevent adherement of the iris to the corneal stroma; therefore permitting the normal formation of the anterior segment. The Krt12rtTA/tetO-TGF-α transgenic mouse line can be a potential model for congenital and secondary glaucoma, while the Krt12rtTA/tet-O-FGF7 transgenic mouse line is a model of OSSN.
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