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 rece ptor (FGFR) are present throughout the adult retina. FGFs are potentia l mitogens, but adult retinal cells are maintained in a nonproliferati ve state unless the retina is damaged. Our work aims to find a modulat or of FGF signaling in normal and pathological retina. We identified a nd sequenced a truncated FGFR1 form from rat retina generated by the u se of selective polyadenylation sites. This 70-kDa form of soluble ext racellular FGFR1 (SR1) was distributed mainly localized in the inner n uclear layer of the retina, whereas the full-length FGFR1 form was det ected in the retinal Muller glial cells. FGF2 and FGFR1 mRNA levels gr eatly increased in light-induced retinal degeneration. FGFR1 was detec ted in the radial fibers of activated retinal Muller glial cells. In c ontrast, SR1 mRNA synthesis followed a biphasic pattern of down- and u p-regulation, and anti-SR1 staining was intense in retinal pigmented e pithelial cells. The synthesis of SR1 and FGFR1 specifically and indep endently regulated in normal and degenerating retina suggests that cha nges in the proportion of various FGFR forms may control the bioavaila bility 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 increase d damaging effects of light by inhibiting endogenous FGF. This study h ighlights the significance of the generation of SR1 in normal and path ological conditions.