Figure 3.

The role of Wnt/β-catenin bi-directional signaling in corneal epithelial stratification. (A) When β-catenin is genetically knocked-down in stromal keratocytes, repression of Bmp4 in the stroma by this pathway is removed. Bmp4 promotes phosphorylation of Smad1/5 and Erk1/2 in the basal corneal epithelial cells, which in turn leads to increased expression of p63, a stem cell marker involved with cell proliferation/stratification. Increased stratification is observed in this model, with 4–5 cell layers by P10. (B) In contrast, in gain-of-function genetic models in which β-catenin is overexpressed by stromal keratocytes, reduced stratification is observed, with only 1–2 cell layers at P21. Bmp4 expression is repressed in the stroma by Wnt signaling, and no longer functions as a paracrine growth factor. The resulting effect is a downregulation of p63 in the epithelium. (C) Epithelial stratification is prevented during early development through Wnt/β -catenin signaling repression of Bmp4. As eyelid opening approaches at P12-P14, Wnt signaling becomes increasingly reduced, allowing for Bmp4 expression in the stroma, resulting in initiation of stratification. Adapted from: (Zhang et al., 2015b).