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F. Majo, S. Vauclair, Y. Barrandon, F. Radtke; Corneal Epithelial Cell Fate Is Maintained During Repair by Notch1 Signaling via Regulation of the Vitamin A Metabolism. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4930.
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We investigated the cell fate differentiation of corneal epithelial cells without the Notch1 gene.
Inactivation of Notch1 in the corneal epithelium of KO mice was analyzed. Expression of keratins 1, 3, 14, of loricrin, Ki67 and CD34 were investigated in the Notch1 KO cornea. The expression of CRBP (specific retinoid-binding proteins) was analyzed in control cornea and Notch1 KO cornea using immunohistochemistry and cell culture. Corneal phenotype of CRBP KO mice with and without wound was also investigated.
Three months after Notch1 inactivation, the central corneal epithelium has become hyperplastic and the cornea has lost its transparency. This hyperplasia is characterized by increased Ki67 staining, disappearance of K3 staining specific to corneal epithelium, and expression of epidermis-specific differentiation markers such as keratin 1 and loricrin. These data suggest that the central corneal epithelium differentiates into a skin-like epidermis in absence of the Notch1 gene. Histological analysis of eyelids from Notch1 deficient mice has revealed defective meibomian glands, necessary to generate a protective lipid layer on the surface of the cornea. We speculated that the absence of meibomian glands leads to chronic ocular surface irritations and generates an epithelial wound healing process that accelerates differentiation to skin like epidermis. We confirmed this hypothesis by suturing lids. Indeed in this case, protection of the eye surface did not result in a cell fate change. In another hand, wounding the corneal epithelium once a week for three weeks accelerated the process of abnormal differentiation. Secondly we demonstrated that Notch1 regulates specific retinoid-binding proteins (CRBP). If Notch1 is inactivated, cellular retinoid-binding protein 1 is missing in the corneal epithelium.
Our results demonstrate that Notch1 is essential for normal cell differentiation during corneal epithelial repair, confirming Notch1 importance in cell fate decisions. Notch1 also regulates CRBP1, which is implicated in cellular metabolic transformation of vitamin A, known to be required to maintain a non keratinized corneal epithelium.
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