Role of Fibroblast Growth Factor Receptor 2 (FGFR2) in Corneal Stromal Thinning

Abstract

Purpose To determine the role of fibroblast growth factor receptor 2 (FGFR2)–mediated signaling in keratocytes during corneal development, a keratocyte-specific FGFR2-knockout (named FGFR2cKO ) mouse model was generated, and its phenotypic characteristics were determined. Methods A FGFR2cKO mouse model was generated by the following method: FGFR2 flox mice were crossed with the inducible keratocyte specific-Cre mice (Kera-rtTA/tet-O-Cre). Both male and female FGFR2cKO- and control mice (1 to 3-months-old) were analyzed for changes in corneal topography and pachymetry maps using the optical coherence tomography (OCT) method. The comparative TUNEL assay and immunohistochemical analyses were performed using corneas of FGFR2cKO and control mice to determine apoptotic cells, and expression of collagen-1 and fibronectin. Transmission electron microscopic analysis was conducted to determine collagen structures and their diameters in corneas of FGFR2cKO and control mice. Results OCT-analyses of corneas of FGFR2cKO mice (n = 24) showed localized central thinning and an increased corneal steepness compared to control mice (n = 23). FGFR2cKO mice further showed a decreased expression in collagen-1, decreased collagen diameters, acute corneal hydrops, an increased fibronectin expression, and an increased number of TUNEL-positive cells suggesting altered collagen structures and keratocytes’ apoptosis in the corneas of FGFR2cKO mice compared to control mice. Conclusions The FGFR2cKO mice showed several corneal phenotypes (as described above in the results) that are also exhibited by the human keratoconus corneas. The results suggested that the FGFR2cKO mouse model serves to elucidate not only the yet unknown role of FGFR2-mediated signaling in corneal physiology but also serves as a model to determine molecular mechanism of human keratoconus development.

Elucidating the mechanism of corneal epithelial cell repair: unraveling the impact of growth factors

“…In addition, the signal transduction of FGFR2b promotes corneal epithelial injury repair, studies have found that FGFR2b knockout mice exhibit reduced proliferation of corneal epithelial cells, as well as loss of lacrimal gland and meibomian gland. FGFR2b is also necessary for the development of submandibular glands ( 119 ). FGF-10 plays a crucial role in the development of the cornea, morphogenesis and growth of the lens and induction and branching of the lacrimal gland and meibomian gland.…”

Animal Models for the Study of Keratoconus

“…Some spontaneously occurring KC-like murine lines have also been noted [30,31]. Additionally, genetic mouse models based on genes of interest to KC have been attempted [33][34][35][36][37][38][39]71]. However, genetic models may not accurately capture cases of KC influenced by environmental factors or other risk factors.…”

“…In the final and most recent publication, by Joseph et al, a stromal keratocyte-specific Fibroblast Growth Factor Receptor 2 (FGFR2) knockout model was described [39]. This model was based on RNA-seq analyses and immunohistochemistry that identified the downregulation of FGFR2 in both normal and KC human corneal fibroblasts [82,83].…”

“…FGF signaling is involved in typical eye development by means of cell differentiation, proliferation, migration, and survival [84]. They propose that FGFR2 may be a factor in KC pathogenesis, acting as an initiator of an FGF signaling cascade that results in keratocyte apoptosis [39]. They hypothesize that this model may allow the study of downstream targets of the FGF signaling pathway as well as keratoconus [39].…”

“…They propose that FGFR2 may be a factor in KC pathogenesis, acting as an initiator of an FGF signaling cascade that results in keratocyte apoptosis [39]. They hypothesize that this model may allow the study of downstream targets of the FGF signaling pathway as well as keratoconus [39]. To examine their model, Joseph et al utilized immunohistochemistry, Western blotting, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, slit-lamp biomicroscopy, SD-OCT, corneal topography, and transmission electron microscopy [39].…”