title: Fibroblast growth factor receptor 2 (FGFR2) is required for corneal epithelial cell proliferation and differentiation during embryonic development.
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, Fgfr2(loxP/loxP) mice (referred as Fgfr2(CKO)) was analyzed to assess changes in cell proliferation, differentiation and survival. We found that Fgfr2(CKO) 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 Fgfr2(CKO) mice. At later stage, cell differentiation markers for corneal epithelium and underlying stromal mesenchyme, keratin-12 and keratocan respectively, were not expressed in Fgfr2(CKO) cornea. Furthermore, Pax6, a transcription factor essential for eye development, was not present in the Fgfr2(CKO) 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.
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Jinglin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Dept. of Ophthalmology, Mason Eye Institute, University of Missouri, Columbia, Missouri, United States of America.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Upadhya
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
authors.affiliation: Dept. of Ophthalmology, Mason Eye Institute, University of Missouri, Columbia, Missouri, United States of America.
authors.forename: Lixing W
authors.initials: LW
authors.lastname: Reneker
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D003315:Cornea / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D004475:Ectoderm / Q000254:growth & development / Q000378:metabolism; D047108:Embryonic Development; D004847:Epithelial Cells / Q000378:metabolism / Q000502:physiology*; D005136:Eye Proteins / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D018398:Homeodomain Proteins / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; C496354:Fgfr2 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2