Abstract
Fibroblast growth factors (FGFs) play important roles in many aspects of embryonic development. During eye development, the lens and corneal epithelium are derived from the same surface ectodermal tissue. FGF receptor (FGFR)-signaling is essential for lens cell differentiation and survival, but its role in corneal development has not been fully investigated. In this study, we examined the corneal defects in Fgfr2 conditional knockout mice in which Cre expression is activated at lens induction stage by Pax6 P0 promoter. The cornea in LeCre, Fgfr2loxP/loxP mice (referred as Fgfr2CKO) was analyzed to assess changes in cell proliferation, differentiation and survival. We found that Fgfr2CKO cornea was much thinner in epithelial and stromal layer when compared to WT cornea. At embryonic day 12.5–13.5 (E12.5–13.5) shortly after the lens vesicle detaches from the overlying surface ectoderm, cell proliferation (judged by labeling indices of Ki-67, BrdU and phospho-histone H3) was significantly reduced in corneal epithelium in Fgfr2CKO mice. At later stage, cell differentiation markers for corneal epithelium and underlying stromal mesenchyme, keratin-12 and keratocan respectively, were not expressed in Fgfr2CKO cornea. Furthermore, Pax6, a transcription factor essential for eye development, was not present in the Fgfr2CKO mutant corneal epithelial at E16.5 but was expressed normally at E12.5, suggesting that FGFR2-signaling is required for maintaining Pax6 expression in this tissue. Interestingly, the role of FGFR2 in corneal epithelial development is independent of ERK1/2-signaling. In contrast to the lens, FGFR2 is not required for cell survival in cornea. This study demonstrates for the first time that FGFR2 plays an essential role in controlling cell proliferation and differentiation, and maintaining Pax6 levels in corneal epithelium via ERK-independent pathways during embryonic development.
Highlights
The cornea is a transparent tissue on the surface of the eye with refractive properties for bending light rays
FGFR2 is required for corneal epithelial cell proliferation during early eye development
In early steps of eye development, Fibroblast growth factors (FGFs)-7 and FGF-10 are expressed in the perioptic mesenchyme, some of these cells migrate into the space between lens and corneal epithelial layer to form the presumptive corneal stroma [20,44]
Summary
The cornea is a transparent tissue on the surface of the eye with refractive properties for bending light rays. The primitive corneal epithelium forms after the lens vesicle detaches from the overlying surface ectoderm. At E14.5–15.5 in the mouse eye, the posterior mesenchymal cells closest to the lens differentiate into a thin layer of corneal endothelium, and the anterior chamber subsequently forms between the lens and cornea. The mesenchymal cells between the corneal epithelium and endothelium begin to differentiate into keratocytes and form corneal stroma. The fully developed cornea is composed of three layers derived from two embryonic germ tissues: a stratified corneal epithelium with surface ectoderm origin on the outer surface, expressing the keratin 3 and 12 (K3/K12) pair [5]; the stromal layer underneath, sparsely populated by keratocytes composed of highly aligned collagen, and the inner surface of the cornea, covered by a single-layer endothelium
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