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Journal of Neuroscience, Vol 16, 1679-1688, Copyright © 1996 by Society for Neuroscience
Retinal degeneration in transgenic mice with photoreceptor-specific expression of a dominant-negative fibroblast growth factor receptor
PA Campochiaro, M Chang, M Ohsato, SA Vinores, Z Nie, L Hjelmeland, A Mansukhani, C Basilico and DJ Zack
Wilmer Ophthalmological Institute, Department of Neuroscience, Johns Hopkins University, Baltimore, Maryland 21287-9277, USA.
Mutant cDNAs coding for dominant-negative forms of the fibroblast growth
factor receptors 1 (FGFR-1) and 2 (FGFR-2) that lack tyrosine kinase
activity were ligated to a 2.2 kb DNA fragment containing the bovine
rhodopsin promoter and used to generate transgenic mice. Six independent
lines were generated with the FGFR-1 construct, and five were generated
with the FGFR-2 construct. Five of the six FGFR-1 mutant lines and all five
FGFR-2 mutant lines showed transgene expression in the retina by reverse
transcription-PCR. By both in situ hybridization and immunohistochemistry,
mutant FGFRs were found to be expressed specifically in photoreceptors of
transgene-positive FGFR-1 and FGFR-2 mice. Lines expressing the FGFR-2
mutant showed progressive photoreceptor degeneration; the retinas showed
minimal or no abnormalities at 1 month, but by 2 months they showed focal
areas of thinning of the outer nuclear layer and disruption of
photoreceptors. By 2-4 months, areas of complete loss of photoreceptors
were seen. These abnormalities were not seen in control littermates not
expressing the transgene. Mice from two FGFR-1 mutant lines showed focal
areas of thinning of the outer nuclear layer and numerous photoreceptors
with fragmented chromatin, whereas the other FGFR-1 lines showed minimal or
no abnormalities. These data indicate that perturbation of FGF signaling in
photoreceptors is associated with progressive photoreceptor degeneration,
suggesting that one or more of the FGFs may act as a survival factor for
photoreceptor cells.
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