Disregulation of ocular morphogenesis by lens-specific expression of FGF-3/int-2 in transgenic mice.
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.
Robinson
M L
ML
Children's Hospital Research Foundation, Columbus, Ohio 43205, USA.
Ohtaka-Maruyama
C
C
Chan
C C
CC
Jamieson
S
S
Dickson
C
C
Overbeek
P A
PA
Chepelinsky
A B
AB
D000818:Animals; D020346:Aquaporins; D002454:Cell Differentiation / Q000502:physiology; D003459:Crystallins / Q000235:genetics; D005123:Eye / Q000166:cytology / Q000196:embryology*; D005136:Eye Proteins / Q000378:metabolism; D051518:Fibroblast Growth Factor 3; D005346:Fibroblast Growth Factors / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007908:Lens, Crystalline / Q000196:embryology; D008562:Membrane Glycoproteins; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000502:physiology*; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis
D020346:Aquaporins; D003459:Crystallins; D005136:Eye Proteins; C489197:Fgf3 protein, mouse; D051518:Fibroblast Growth Factor 3; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C030328:aquaporin 0; D005346:Fibroblast Growth Factors