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A. R. Djalilian, A. Ito, S. Balali, C. Choe, M. Gupta, R. M. Lavker, B. Y. J. T. Yue; Increased Corneal Epithelial Proliferation Results in Down-Regulation of Notch Signaling. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2728.
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Recent studies have implicated Notch signaling in corneal epithelial growth and differentiation. In this study we evaluated the expression and activation of Notch pathway genes during both corneal epithelial wound healing and a chemically induced hyperproliferative state.
The central corneal epithelium was debrided in adult C57BL/6 mice, and corneas were harvested at 24, 48, and 144 hrs post-debridement. As an alternative to debridement, mice were treated with topical phorbol myristate ester, which is known to induce proliferation of the corneal epithelial cells. The expression of Notch pathway genes was evaluated by RT-PCR. The expression of Notch1 and Jagged1 protein was also evaluated by immunofluorescence. Notch activation was assessed by measuring the levels of the Notch intracellular domain (NICD) by western blotting.
Expression of Notch pathway genes including Notch1, Notch2, Delta1, Jagged1, Jagged2, and the downstream target gene Hes1 was markedly lower 24 hrs post-wounding. The mRNA expression partially returned toward baseline at 48 hrs and was completely back to baseline by 6 days. The expression of Notch1 and Jag1 protein by immunofluorescence was qualitatively decreased 1 day after wounding. NICD levels were also decreased 24 hrs post-wounding and after application of topical phorbol myristate.
These results suggest that Notch signaling is down-regulated during the early stages of hyperproliferation. This is consistent with previous studies which have found Notch activation to induce growth arrest.
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