Fibroblast growth factor (FGF) soluble receptor 1 acts as a natural inhibitor of FGF2 neurotrophic activity during retinal degeneration.
Fibroblast growth factors (FGF) 1 and 2 and their tyrosine kinase receptor (FGFR) are present throughout the adult retina. FGFs are potential mitogens, but adult retinal cells are maintained in a nonproliferative state unless the retina is damaged. Our work aims to find a modulator of FGF signaling in normal and pathological retina. We identified and sequenced a truncated FGFR1 form from rat retina generated by the use of selective polyadenylation sites. This 70-kDa form of soluble extracellular FGFR1 (SR1) was distributed mainly localized in the inner nuclear layer of the retina, whereas the full-length FGFR1 form was detected in the retinal Muller glial cells. FGF2 and FGFR1 mRNA levels greatly increased in light-induced retinal degeneration. FGFR1 was detected in the radial fibers of activated retinal Muller glial cells. In contrast, SR1 mRNA synthesis followed a biphasic pattern of down- and up-regulation, and anti-SR1 staining was intense in retinal pigmented epithelial cells. The synthesis of SR1 and FGFR1 specifically and independently regulated in normal and degenerating retina suggests that changes in the proportion of various FGFR forms may control the bioavailability of FGFs and thus their potential as neurotrophic factors. This was demonstrated in vivo during retinal degeneration when recombinant SR1 inhibited the neurotrophic activity of exogenous FGF2 and increased damaging effects of light by inhibiting endogenous FGF. This study highlights the significance of the generation of SR1 in normal and pathological conditions.
Développement, Vieillissement et Pathologie de la Rétine, Institut National de la Santé et de la Recherche Médicale U450, Affiliée Centre National de la Recherche Scientifique, Association Claude Bernard, 75016 Paris, France.
X
X
Guillonneau
F
F
Régnier-Ricard
O
O
Laplace
L
L
Jonet
M
M
Bryckaert
Y
Y
Courtois
F
F
Mascarelli
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism; D005091:Exons; D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D005786:Gene Expression Regulation / Q000528:radiation effects; D006801:Humans; D008027:Light / Q000009:adverse effects; D051379:Mice; D008969:Molecular Sequence Data; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology; D012160:Retina / Q000166:cytology / Q000502:physiology* / Q000503:physiopathology; D012162:Retinal Degeneration / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D014158:Transcription, Genetic / Q000528:radiation effects
D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases