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C.-Y. Liu, M. Call, Y. Zhang, W. W. Kao; The Role of β-catenin Signaling in Ocular Surface Homeostasis and Tumorigenesis. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2594.
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© ARVO (1962-2015); The Authors (2016-present)
β-catenin signaling has been implicated in two major biological processes of embryonic development and tumorigenesis. In this study, we determined the role of β-catenin in corneal epithelial morphogenesis, homeostasis, and tumorigenesis.
Conditional gain- and loss-of-function mutations of the β-catenin gene (Ctnnb1) were specifically expressed in differentiated corneal epithelium, respectively, in vivo.
Dox-treated Krt12rtTA/w;tetO-Cre;Ctnnb1floxedEx3/w triple transgenic mice all exhibited corneal epithelial hyperplasia at different developmental stages from E18.5 to P30. Immunofluorescent staining showed that nuclear localization of β-catenin correlated well with the hyperplastic transformation. These corneal epithelial hyperplastic lesions loss K12 expression, but maintain high level of p63. The basement membrane components i.e., laminins-1 and -β1 are completely down-regulated. Interestingly, members involved in sonic hedgehog signaling Shh, Smo, and Ptc were all dramatically down-regulated. Moreover, X-gal positive cells completely correlated with the hyperplastic transformation and stromal invasion in the cornea of Dox-induced Krt12rtTA/w;tetO-Cre;Ctnnb1floxed Ex3/w;TOPGAL quadruple transgenic mice. On the other hand, loss of β-catenin from the corneal epithelium did not result in significant abnormality, suggesting that β-catenin is dispensable for the maintenance of corneal epithelial homeostasis. However, conditional ablation of β-catenin in Krt12rtTA/rtTA;tetO-FGF-7;tetO-Cre;Ctnnb1f/f mice treated with Dox prevents corneal epithelial hyperplastic transformation.
Forced expression of dominant stabilizing mutant β-catenin disrupts corneal homeostasis and leads to hyperplastic transformation, whereas ablation of β-catenin protects against FGF-7-induced corneal hyperplasia. These results suggest that regulation of β-catenin signaling plays a pivotal role in the maintenance of normal corneal epithelial homeostasis.
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