Disregulation of Ocular Morphogenesis by Lens-Specific Expression of FGF-3/Int-2 in Transgenic Mice

Abstract

FGF-3, originally named int-2, was discovered as an oncogene frequently activated in mammary carcinomas resulting from the chromosomal integration of the mouse mammary tumor virus (MMTV). Int-2 was later designated FGF-3 based on sequence homology with other members of the fibroblast growth factor (FGF) family. FGF-1 is the prototypical member of the FGF family, and is the only family member which activates all known FGF receptor isoforms. Transgenic mice expressing in the lens a form of FGF-1 engineered to be secreted show premature differentiation of the entire lens epithelium. In contrast, transgenic mice engineered to secrete FGF-2 in the lens do not undergo premature differentiation of the lens epithelium (C. M. Stolen et al., 1997, Development 124, 4009-4017). To further assess the roles of FGFs and FGF receptors in lens development, the alpha A-crystallin promoter was used to target expression of FGF-3 to the developing lens of transgenic mice. The expression of FGF-3 in the lens rapidly induced epithelial cells throughout the lens to elongate and to express fiber cell-specific proteins including MIP and beta-crystallins. This premature differentiation of the lens epithelium was followed by the degeneration of the entire lens. Since FGF-1 and FGF-3 can both activate one FGF receptor isoform (FGFR2 IIIb) that is not activated by FGF-2, these results suggest that activation of FGFR2 IIIb is sufficient to induce fiber cell differentiation throughout the lens epithelium in vivo. Furthermore, transgenic lens cells expressing FGF-3 were able to induce the differentiation of neighboring nontransgenic lens epithelial cells in chimeric mice. Expression of FGF-3 in the lens also resulted in developmental alterations of the eyelids, cornea, and retina, and in the most severely affected transgenic lines, the postnatal appearance of intraocular glandular structures.

Activated Ras induces lens epithelial cell hyperplasia but not premature differentiation

“…4). The anterior cells did not elongate as seen in FGF-overexpressing lenses (Robinson et al, 1995b;Robinson et al, 1998), nor did they exit from the cell cycle. Instead, BrdU incorporation assays showed that there was a two-fold increase of S-phase cells in the Rastransgenic lenses when compared to nontransgenic lenses (Fig.…”

Ectopic expression of FGF-3 results in abnormal prostate and Wolffian duct development

“…When targeted to adult organs (i.e. mammary glands, male reproductive tract, lens of eyes and lungs), FGF-3 induces epithelial hyperplasia (Muller et al, 1990;Ornitz et al, 1991;Stamp et al, 1992;Robinson et al, 1998;Zhao et al, 2001). Taken together, these studies demonstrate that if FGF-3 is inappropriately expressed, it may activate dormant pathways that can then severely perturb normal growth and development.…”

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

“…Treatment of cultured lens epithelial explants with FGF1 or FGF2 stimulates cell proliferation at lower doses and fiber cell differentiation at higher doses McAvoy, 1987, 1989;McAvoy and Chamberlain, 1989;Schulz et al, 1993;Le and Musil, 2001). Overexpression of FGF1,3,4,7,8,or 9 in the lens fiber cells of transgenic mice causes the neighboring epithelial cells to transform into fiber-like cells in vivo (Lovicu and Overbeek, 1998;Robinson et al, 1998).…”