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Abstract #52711 Published in IGR 15-1
Targeted overexpression of TGF-α in the corneal epithelium of adult transgenic mice induces changes in anterior segment morphology and activates noncanonical Wnt signaling
Yuan Y; Yeh LK; Liu H; Yamanaka O; Hardie WD; Kao WW; Liu CYInvestigative Ophthalmology and Visual Science 2013; 54: 1829-1837
PURPOSE: Transforming growth factor-alpha (TGF-α) transduces its signal through the epidermal growth factor receptor and is essential for corneal epithelial homeostasis. Previous studies have demonstrated that overexpression of TGF-α in the developing eye leads to anterior segment dysgenesis. However, the underlying mechanisms remain unclear. Here we examined the effects of TGF-α overexpression on adult ocular surface homeostasis. METHODS: Binary Tet-On transgenic Krt12(rtTA)/tet-O-TGF-α mice were subjected to doxycycline (Dox) induction to overexpress TGF-α in the corneal epithelium. Intraocular pressure (IOP) was measured by noninvasive tonometry. The enucleated eyes of the experimental mice were subjected to histopathology, immunohistochemistry, and biochemistry examination. RESULTS: Histologic and immunofluorescent examination showed that double-transgenic mice overexpressing TGF-α manifested peripheral anterior synechiae. Elevation of IOP, activation of glial cells, and loss of retinal ganglion cells were also observed. Quantitative real-time PCR revealed that the expressions of genes (RXRα, PITX2, and FOXC1) related to anterior segment dysgenesis were downregulated. Canonical Wnt signaling was suppressed, whereas noncanonical Wnt ligands (Wnt4 and Wnt5a) were upregulated. Increased myosin light chain phosphorylation suggested that noncanonical Wnt signaling is activated in affected eyes. CONCLUSIONS: Overexpression of TGF-α in the corneal epithelium induces changes in anterior segment morphology. Corneal endothelial abnormalities are associated with the activation of the noncanonical Wnt and RhoA/ROCK signaling axis, indicating a potential application of RhoA/ROCK inhibitors as a therapeutic strategy for certain types of secondary angle-closure glaucoma.
Crawley Vision Research Laboratory, Department of Ophthalmology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
Full articleClassification:
3.6 Cellular biology (Part of: 3 Laboratory methods)
3.5 Molecular biology incl. SiRNA (Part of: 3 Laboratory methods)
2.4 Anterior chamber angle (Part of: 2 Anatomical structures in glaucoma)
5.1 Rodent (Part of: 5 Experimental glaucoma; animal models)