Fibroblast Growth Factor (FGF) Soluble Receptor 1 Acts as a Natural Inhibitor of FGF2 Neurotrophic Activity during Retinal Degeneration

Abstract

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.

Both FGF1 and Bcl-x synthesis are necessary for the reduction of apoptosis in retinal pigmented epithelial cells by FGF2: role of the extracellular signal-regulated kinase 2

“…Previous studies have suggested that endogenous FGFs act as protection factors in vivo by showing a dramatic upregulation of FGF gene expression in response to cell death in various retinal degeneration models (Portera-Gailleau et al, 1994;Gao and Holly®eld, 1996). We have con®rmed that this is the case in retina, by demonstrating that inhibition of the binding of endogenous FGFs to their receptors accelerates and increases retinal cell apoptosis (Guillonneau et al, 1998a). More recently, inhibition of FGF1 by antisense ODNs in embryonic chick retinal cells in vitro and in vivo has been shown to inhibit neuron survival (De sire et al, 1998).…”

Matrix metalloproteinases are required for retinal ganglion cell axon guidance at select decision points

“…We observed that GM6001 inhibited FGF2 stimulated RGC neurite extension in vitro (data not shown), which suggests a scenario where an MMP-cleaved FGFR ectodomain would function to promote FGF2 actions on RGC axons. In general, however, soluble FGFR ectodomains are thought to act as inhibitors of FGF signalling (Celli et al, 1998;Guillonneau et al, 1998;Mandler and Neubuser, 2004). Possibly, then, the GM6001/SB-3CT mechanism involves blocked cleavage of heparan sulfate proteoglycans (HSPGs) by growth cone metalloproteinases.…”

Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1

“…Furthermore, FGFR1 immunoreactivity, normally concentrated in photoreceptor cell bodies, 56 dramatically increased throughout the retina of diabetic rats, mainly in the inner retina, a localization pattern consistent with its reported presence in activated Müller cells. 57 Increased levels of HSPG and of AAV2 co-receptors are not unexpected in DR and may contribute to its progression. High glucose levels upregulate cell-associated proteoglycans in retinal pericytes 58 and promote the secretion of HS chains by endothelial cells, 59 and VEGF increases the retinal expression of the HS side chains of HSPGs.…”