The Wnt/β-catenin pathway is required for the proper development of the cornea.
19,97,98 During mouse corneal development, Wnt ligands are expressed throughout the presumptive epithelium.
56 Increased expression of
Wntless and
Porc indicate that Wnt signaling may also exert paracrine effects to the stroma. This is supported by reports of expression of Fzd receptors and activation of Wnt signaling in the stromal mesenchyme and corneal endothelium.
56,99 Although Wnt ligands were uniformly upregulated, there was a clear distinction in the differential expression of
Fzd. Fzd4 and
Fzd10 are associated with the Wnt/β-catenin pathway, whereas
Fzd3 and
Fzd6 are involved in the Wnt/PCP pathway.
100–103 Fzd4 is required for retinal angiogenesis and implicated in corneal neovascularization.
104,105 Fzd3 is involved in neural crest induction and migration.
106–108 Reduced expression of
Fzd4 and
Fzd3 and upregulation of
Fzd10 and
Fzd6 may be required for corneal cell differentiation and avascularity.
100–103,109–111 Despite upregulation of Wnt ligands and receptors, our data suggest that Wnt/β-catenin signaling is inhibited at multiple levels. This complements previous observations that active Wnt/β-catenin signaling is absent in the corneal epithelium at E14.5 and E16.5, and it is progressively reduced in the stroma until postnatal day 3.
99 This downregulation is critical for proper development of the cornea.
19,97,98 In contrast, our data suggest that noncanonical Wnt pathways are upregulated. The Wnt/PCP and Wnt/Ca pathways have been studied during the formation of the eye field and retinogenesis,
112 but their roles in the cornea are not clear. Our data indicate an increase in the components of the Wnt/PCP pathway, including
Wnt4,
Wnt5a, and
Fzd6.
100,113,114 In adults, the Wnt/PCP pathway is important for corneal homeostasis and also guides directional migration of epithelial cells during wound healing.
110 Wnt/PCP signaling is also involved in cell differentiation, collagen orientation, cell alignment, and axon guidance,
115–117 all of which are required for proper corneal development.