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T. Kazuto, Y. Hayashi, T.–I. Chikama, N. Terai, W.W. Y. Kao; The Mechanism of Corneal Epithelium Wound Healing Delay in TGF–Beta Type II Receptor Conditional Knock–Out Mice . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5028.
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© ARVO (1962-2015); The Authors (2016-present)
We previously reported that healing of epithelium debridement was delayed in mouse cornea epithelium lacking TGF–ß type II receptor (Tbr2) by conditional knock–out, due to inhibition of cell migration suppression albeit an up–regulation of cell proliferation The purpose of this study is to determine molecular mechanisms accountable for the observations.
TGF–ß type II receptor (Tbr2) floxed mice were bred with Krt12–Cre mice to generate bitransgenic mice in which the TGF–ß receptor 2 gene (Tbr2) was disrupted selectively in the corneal epithelial cells. Corneal epithelial debridement (2 mm diameter) was created in 2–month–old bitransgenic Tbr2ceΔ/ceΔ (Krt12Cre/CreTbR2f/f) mice and their littermates as controls Tbr2ceΔ/w (Krt12Cre/CreTbR2f/w) and Tbr2w/w (Krt12Cre/CreTbR2w/w). Immunohistochemistry with anti–p–cJun and ActivinR1B antibody was performed to elucidate their roles in wound healing. Smad4 floxed mice were also bred with Krt12–Cre mice to generate bitransgenic mice in which the Smad4 gene was disrupted selectively in the corneal epithelial cells. Corneal epithelial debridement was created in 2–month–old bitransgenic Smad4ceΔ/ceΔ (Krt12Cre/CreSmad4f/f) mice and their littermates as controls Smad4ceΔ/w (Krt12Cre/CreSmad4f/w) and Smad4w/w (Krt12Cre/CreSmad4w/w).
The result of phospo–cJun immunohistochemistry shows that cJun activation in early phase of corneal epithelium wound healing is suppressed in Tbr2ceΔ/ceΔ mice than those of littermate controls. The result of activin R1B immunohistochemistry shows a prolong up–regulation of activin R1B expression up to 48 h after wounding in Tbr2ceΔ/ceΔ whereas in controls the up–regulation of activin R1B returned to basal level by 48 hrs of wounding. Smad4ceΔ/ceΔ mice did not show any wound healing delay comparing with controls.
Our results indicate that Smad cascade does not play a significant role in corneal epithelium wound healing. Our data are consistent with the notion that p38 activation mediates the TGFß signaling, which may account for cell migration and inhibition of cell proliferation during healing of epithelium debridement.
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