Fibroblast growth factor receptor 2 (Fgfr2) plays an important role in eyelid and skin formation and patterning

Abstract

Initiating as protruding ridges above and below the optic vesicle, the eyelids of mice grow across the eye and temporarily fuse in fetal life. Mutations of a number of genes disrupt this developmental process and result in a birth defect, "open-eyelids at birth." Here we show that a critical event for eyelid induction occurs at embryonic day 11.5 (E11.5) when the single cell-layered ectoderm in the presumptive eyelid territory increases proliferation and undergoes morphologic transition to form cube-shaped epithelial cells. Using embryos lacking the Fgfr2 Ig domain III (Fgfr2 ⌬III/⌬III ) generated by tetraploid rescue and chimeric embryo formation approaches, we demonstrate that this event is controlled by Fgfr2 signals as the Fgfr2 ⌬III/⌬III mutation blocks these changes and results in embryos without eyelids. Fgfr2 and its ligands are differentially expressed in the ectoderm and underlying mesenchyme and function in a reciprocal interacting loop that specifies eyelid development. We also demonstrate that similar defects account for failure of skin formation at early stages. Interestingly, Fgfr2-independent skin formation occurs at E14.5 mutant embryos, resulting in much thinner, yet well-differentiated epidermis. Notably, mutant skin remains thin with decreased hair density after transplantation to wild-type recipients. These data demonstrate an essential role of Fgfr2 in eyelid and skin formation and patterning. Published 2001 Wiley-Liss, Inc. †

Signaling through FGF receptor‐2 is required for lens cell survival and for withdrawal from the cell cycle during lens fiber cell differentiation

“…As described previously in mice chimeric for Fgfr2 (Li et al, 2001) or that carried homozygous deletion of the b isoform of Fgfr2 (De Moerlooze et al, 2000), eyes from Cre-positive, Fgfr2 loxP/loxP embryos showed defective eyelid formation and failure of eyelid closure. Because LeCre is expressed within and around the lens placode, the surface ectoderm cells that give rise to the eyelids also lack Fgfr2.…”

“…Previous studies of embryos with germ line deletion of Fgfr3 or Fgfr4, or chimeric mouse embryos with deletion of Fgfr1 (Zhao et al, manuscript submitted for publication) or Fgfr2 (Li et al, 2001) did not report lens phenotypes. In the present experiments, we targeted floxed Fgfr2 using a Cre transgene that can delete target genes in all lens cells beginning at embryonic day (E) 9.0 (Ashery- Padan et al, 2000).…”

A dual role of FGF10 in proliferation and coordinated migration of epithelial leading edge cells during mouse eyelid development

“…1. They include the following: initiation (ectoderm morphogenesis and groove formation; E11.5), eyelid mesenchymal protrusion (E13.5), protruding epithelial ridge formation at the tip of the eyelid margin (E15) and subsequent extension of the upper and lower eyelid epithelium first (E15~16) and mesenchymal cells later (E16.5~17.5) (Li et al, 2001;Stepp, 1999). The upper and lower eyelid fusion occurs in the epithelium, and the mesenchymal cells are not fused for subsequent reopening.…”

“…In mice, eyelid formation begins on day 11.5 of gestation (E11.5), and from E14 to 16 the eyelids grow, flatten across the eye, progressively meet beginning at the inner and outer canthi and fuse tightly with each other (Harris and McLeod, 1982;Li et al, 2001). The eyelashes and the glands lying along the margins of the lids start to differentiate from this common epithelial lamina before the lids reopen at 14 days after birth (Findlater et al, 1993).…”

“…Mutations at several distinct loci have been found to cause such open-eyelids, often as part of a syndrome with other defects. For example, open-eyelids results from spontaneous or gene-knockout mutation at the loci of transforming growth factor α (Tgfa), its receptor epidermal growth factor receptor (Egfr), activin/inhibin βB (Inhbb -Mouse Genome Informatics) fibroblast growth factor receptor type 2b (Fgfr2b), Jun, MEK kinase 1 and some forkhead genes (Luetteke et al, 1993;Mann et al, 1993;Miettinen et al, 1999;Thereadgill et al, 1995;Vassalli et al, 1994;Celli et al, 1998;De Moerlooze et al, 2000;Li et al, 2001;Li et al, 2003;Zenz et al, 2003;Zhang et al, 2003;Kume et al, 1998;Uda et al, 2004). However, the molecular and cellular events occurring during eyelid development and the interactions among the signaling molecules have not been fully elucidated.…”