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J. Huang, D. C. Beebe; Fgf Signaling Through Fgf Receptor-2 Is Required for Eyelid Closure and Regulates Hedgehog, Wnt and Bmp Signaling. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1320. doi: https://doi.org/.
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The mouse eyelid closes at embryonic day (E) 16.5 by fusion of the upper and lower eyelid epithelium. Mutations in FGF10, EGF receptors or ligands, Wnt signaling antagonists, or one of several transcription factors leads to eyelid open at birth (EOB) in mice. However, the signaling hierarchy controlling eyelid closure has not been worked out. The purpose of this study was to delineate the molecules downstream of FGF signaling that are required for eyelid closure.
Fgfr2 was deleted from the eyelid epithelium by crossing Le-Cre mice with Fgfr2 floxed mice. Cell proliferation and death in wild type and mutant eyelid epithelial cells was compared by BrdU and TUNEL labeling. Expression of candidate genes known or proposed to be essential for eyelid closure was examined by in situ hybridization and immunostaining in wild type and mutant mice. Activation of the canonical Wnt signaling pathway was evaluated by β-galactosidase staining in TOPGAL mice. Sonic hedgehog (Shh) signaling was blocked by treating cultured eyelids with the Shh antagonist cyclopamine.
Deletion of Fgfr2 from the eyelid epithelium resulted in EOB, with reduced epithelial cell proliferation, but no effect on cell death. FGF signaling through Fgfr2 induced Shh expression. Expression of secreted frizzle-related protein-1 (Sfrp1), an antagonist of Wnt signaling, was blocked by cyclopamine and is, therefore, dependent on Shh signaling. Loss of Sfrp1 expression increased canonical Wnt signaling in eyelid epithelial cells. Signaling through Fgfr2 also stimulated BMP expression in subepithelial mesenchymal cells. Conditional deletion of type I BMP receptors also resulted in EOB. The pathways regulated by BMP signaling are under investigation and will be presented.
Signaling through FGF receptor-2 is required for eyelid closure. FGF signaling controls a complex network of signaling molecules, including members of the Shh, Wnt and BMP pathways.
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