Spatiotemporal dynamics of canonical Wnt signaling during embryonic eye development and posterior capsular opacification (PCO)

Abstract

The appropriate spatial and temporal regulation of canonical Wnt signaling is vital for eye development. However, the literature often conflicts on the distribution of canonical Wnt signaling in the eye. Here, using a sensitive mouse transgenic reporter line, we report a detailed re-evaluation of the spatiotemporal dynamics of canonical Wnt signaling in the developing eye. Canonical Wnt activity was dynamic in the optic vesicle and later in the retina, while it was absent from the ectodermal precursors of the lens and corneal epithelium. However, later in corneal development, canonical Wnt reporter activity was detected in corneal stroma and endothelium precursors as they form from the neural crest, although this was lost around birth. Interestingly, while no canonical Wnt signaling was detected in the corneal limbus or basal cells at any developmental stage, it was robust in adult corneal wing and squamous epithelial cells. While canonical Wnt reporter activity was also absent from the postnatal lens, upon lens injury intended to model cataract surgery, it upregulated within 12 h in remnant lens epithelial cells, and co-localized with alpha smooth muscle actin in fibrotic lens epithelial cells from 48 h post-surgery onward. This pattern correlated with downregulation of the inhibitor of canonical Wnt signaling, Dkk3. These data demonstrate that canonical Wnt signaling is dynamic within the developing eye and upregulates in lens epithelial cells in response to lens injury. As canonical Wnt signaling can collaborate with TGFβ to drive fibrosis in other systems, these data offer the first evidence in a lens-injury model that canonical Wnt may synergize with TGFβ signaling to drive fibrotic posterior capsular opacification (PCO).

Transformation of the Transcriptomic Profile of Mouse Periocular Mesenchyme During Formation of the Embryonic Cornea

“…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.…”

“…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.…”

A new transgenic reporter line reveals Wnt-dependent Snail2 reexpression and cranial neural crest differentiation in Xenopus

“…At stage ~42, Wnt was active in the differentiating head cartilage structures, cranial nerves, olfactory epithelium, eye and brain ( Fig. 5E, E'), consistent with previously reported activities and/or functions of Wnt signaling in these tissues in mice [34][35][36][37] . These patterns are also strikingly similar to those of eGFP in the snail2::egfp embryos as well as endogenous Snail2 mRNA and protein, suggesting a possible role for Wnt signaling in inducing snail2 expression, not only in the pre-migratory and migrating CNC but also in the differentiating CNC, in X. tropicalis embryos.…”

Aniridia-related Keratopathy Relevant Cell Signaling Pathways in Human Fetal Corneas

“…9,12 Notch1, Wnt/β-catenin, SHH, and mTOR cell signaling pathways are essential for eye development, regulate both cell proliferation and homeostasis in mammals and are altered in ARK corneas. 7,[13][14][15][16] The Notch1 signaling pathway coordinates corneal epithelial repair, vertical migration and regulation of basal corneal epithelial cells. 35 In the central corneal epithelium, these processes depend on transient amplifying cells (TAC), which have high migratory and proliferative capacity.…”

“…7 Determination of limbal stem cell fate is regulated by the Notch1 and Wnt/β-catenin signaling pathways and are essential during normal tissue development and regeneration. 16,20 The extracellular ligands Wnt5a and Wnt7a stimulate the Wnt/β-catenin signaling cascade, which leads to proliferation of corneal limbal stem cells 21 , and is increased in ARK corneas. 7 β catenin is important for the regulation of epithelial differentiation and stratification.…”