Corneal Epithelial Cell Fate Is Maintained during Repair by Notch1 Signaling via the Regulation of Vitamin A Metabolism

Abstract

Integrity and preservation of a transparent cornea are essential for good vision. The corneal epithelium is stratified and nonkeratinized and is maintained and repaired by corneal stem cells. Here we demonstrate that Notch1 signaling is essential for cell fate maintenance of corneal epithelium during repair. Inducible ablation of Notch1 in the cornea combined with mechanical wounding show that Notch1-deficient corneal progenitor cells differentiate into a hyperplastic, keratinized, skin-like epithelium. This cell fate switch leads to corneal blindness and involves cell nonautonomous processes, characterized by secretion of fibroblast growth factor-2 (FGF-2) through Notch1(-/-) epithelium followed by vascularization and remodeling of the underlying stroma. Vitamin A deficiency is known to induce a similar corneal defect in humans (severe xerophthalmia). Accordingly, we found that Notch1 signaling is linked to vitamin A metabolism by regulating the expression of cellular retinol binding protein 1 (CRBP1), required to generate a pool of intracellular retinol.

Transcription Factor PAX6 (Paired Box 6) Controls Limbal Stem Cell Lineage in Development and Disease

“…The influence of Wnt signaling on ocular surface development has also been extensively reported. Wnt4 is expressed in human fetal corneas and adult basal LSCs (26). DKK2, an antagonist of canonical Wnt signaling, is required for accurate development of the ocular surface epithelium in mice by regulation of Wnt/␤-catenin activity (14).…”

RBP-Jκ-dependent Notch signaling enhances retinal pigment epithelial cell proliferation in transgenic mice

“…In this study, we asked whether Notch activity in RPE cells would promote cell proliferation or rather function as a tumor suppressor and induce cell differentiation as in skin and corneal epithelia (Nicolas et al, 2003;Ma et al, 2007;Vauclair et al, 2007;Dotto, 2008). We genetically show that Notch signaling in the RPE is dependent on the transcription factor RBP-Jk.…”

Primary cilia maintain corneal epithelial homeostasis by regulation of the Notch signaling pathway

“…Disruption of the Notch pathway in K14-and K15-(Krt15) expressing cells by ablation of the Notch1 receptor induces hyperplasia of basal CECs, cell fate change into skin-like tissue, and formation of an opaque plate at the center of the cornea (Vauclair et al, 2007). Although hyperplasia is consistent with the phenotype observed in the CE of the cilia-deficient mutants, we did not detect changes in cell fate or formation of corneal plaque (Fig.…”

“…Interestingly, in the ocular surface Notch activation contributes to the maintenance of the stratified and non-keratinized corneal and conjunctival cells differentiation and function (Djalilian et al, 2008;Ma et al, 2011;Nakamura et al, 2008;Vauclair et al, 2007;Xiong et al, 2011;Zhang et al, 2013). This led us to hypothesize that primary cilia could play an important role in maintaining CE homeostasis and/or morphogenesis.…”