Dkk2 plays an essential role in the corneal fate of the ocular surface epithelium

Abstract

The Dkk family of secreted cysteine-rich proteins regulates Wnt/β-catenin signaling by interacting with the Wnt co-receptor Lrp5/6. Here, we show that Dkk2-mediated repression of the Wnt/β-catenin pathway is essential to promote differentiation of the corneal epithelial progenitor cells into a non-keratinizing stratified epithelium. Complete transformation of the corneal epithelium into a stratified epithelium that expresses epidermal-specific differentiation markers and develops appendages such as hair follicles is achieved in the absence of the Dkk2 gene function. We show that Dkk2 is a key regulator of the corneal versus epidermal fate of the ocular surface epithelium.

Function and biological roles of the Dickkopf family of Wnt modulators

“…In fact, in the absence of Dkk2 there occurs a complete transformation of the corneal epithelium into a stratified epithelium that expresses epidermal-specific differentiation markers and develops appendages such as hair follicles. Analysis of Wnt reporter in these mutants indicates that the loss of Dkk2 activates Wnt/b-catenin signaling (Mukhopadhyay et al, 2006). Furthermore, conditional ablation of Notch1 leads to a similar phenotype in mice, which is also due to activation of the Wnt pathway (Nicolas et al, 2003).…”

“…In contrast, Dkk2 null mutant mice are viable but they are blind, because they grow hair on their cornea (Mukhopadhyay et al, 2006). In fact, in the absence of Dkk2 there occurs a complete transformation of the corneal epithelium into a stratified epithelium that expresses epidermal-specific differentiation markers and develops appendages such as hair follicles.…”

The Wnt pathway and the roles for its antagonists, DKKS, in angiogenesis

“…Dkk-2 2/2 mice, in contrast with Dkk-1 1/2 mice (71), show decreases in bone mineral density and osteopenia owing to defects in mineralization (72). Dkk-2 2/2 mice are blind owing to the transformation of corneal epithelium into a stratified epithelium (73). Recently, we demonstrated that endothelial cell-specific expression of Dkk-2 leads to a retinal vascular phenotype opposite that of Dkk-1.…”

Niche regulation of corneal epithelial stem cells at the limbus

“…Recently, mouse null for expression of the Dickkopf (Dkk) family number Dkk2, one of the Wnt pathway inhibitors, was shown to lose the corneal fate decision on the ocular surface to epidermal differentiation [120]. As a result, Wnt/b-catenin pathway is upregulated in the limbal, but not corneal, mesenchyme, indicating that Dkk2 acts by inhibiting Wnt signaling in the limbal stroma [120], providing the first evidence for a limbal mesenchymal (niche) role in limbal SC differentiation during morphogenesis. Because expression of PAX 6 is lost in the Dkk2-null corneal epithelium, it is likely that Dkk2 might be an upstream regulator dictating PAX 6 expression in the ocular surface epithelium.…”