Disregulation of ocular morphogenesis by lens-specific expression of FGF-3/int-2 in transgenic mice

Dev Biol. 1998 Jun 1;198(1):13-31. doi: 10.1006/dbio.1998.8879.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Aquaporins
  • Cell Differentiation / physiology
  • Crystallins / genetics
  • Eye / cytology
  • Eye / embryology*
  • Eye Proteins / metabolism
  • Fibroblast Growth Factor 3
  • Fibroblast Growth Factors / physiology*
  • Gene Expression Regulation, Developmental / genetics*
  • Immunohistochemistry
  • In Situ Hybridization
  • Lens, Crystalline / embryology
  • Membrane Glycoproteins*
  • Mice
  • Mice, Transgenic
  • Morphogenesis / physiology*
  • Phenotype
  • Proto-Oncogene Proteins / physiology*
  • RNA, Messenger / analysis

Substances

  • Aquaporins
  • Crystallins
  • Eye Proteins
  • Fgf3 protein, mouse
  • Fibroblast Growth Factor 3
  • Membrane Glycoproteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • aquaporin 0
  • Fibroblast Growth Factors