Fibroblast growth factor receptor deficiency in dystrophic retinal pigmented epithelium

Abstract

The retinal pigmented epithelium (RPE) is known to be the site of the primary lesion in inherited retinal dystrophy in the Royal College of Surgeons (RCS) rat, a model for retinitis pigmentosa. Although the only functional defect so far detected in these cells is their failure to efficiently phagocytose shed photoreceptor outer segment debris, the actual cause of photoreceptor cell death is still unknown. Recently the possibility of "trophic factors" important in photoreceptor survival produced by normal RPE but not by dystrophic RPE has been suggested. Hence we decided to investigate the presence and abundance of two candidate diffusible factors, the acidic and basic fibroblast growth factors (aFGF and bFGF, respectively), as well as their high affinity cell surface receptors (FGF-R). mRNA was isolated from primary cultures of purified normal and dystrophic RPE and analyzed by PCR amplification using specific oligonucleotide primers for aFGF and bFGF: the size and abundance of amplified fragments was similar for both cell types. Also, aFGF protein, detected by immunocytochemistry using specific antisera, appeared to be present in approximately equal amounts and distributed in a similar pattern. However, scatchard analysis of radio-labelled bFGF binding to primary cultures of normal and dystrophic rat RPE revealed that dystrophic RPE possess only 29% the number of surface receptors compared to congenic normal cells. Furthermore, the level of expression of FGF-R2 mRNA, but not that of FGF-R1, was significantly different. Other parameters measured (receptor affinity, profile of ligand internalization and degradation, receptor molecular weight and mitogenic activity) did not show any significant differences between normal and dystrophic RPE. The precise role of FGF-R deficiency in the etiology of the disease hence remains to be determined, but it indicates the importance of trophic factors in the normal functioning of the retina.

In Vivo Involvement of Heparan Sulfate Proteoglycan in the Bioavailability, Internalization, and Catabolism of Exogenous Basic Fibroblast Growth Factor

“…Our data have also shown that the labeling gradually decreased and almost completely disappeared in some organs 5 days postinjection of 14 C-FGF2, suggesting that FGF2 is under continuous cellular internalization, intracellular catabolism, and recycling of the resulting amino acids. The catabolic fragments of FGF2 that we have demonstrated in our study were similar in all organs and to those seen in FGF2 internalization and catabolism in vitro (Malecaze et al, 1993;Colin et al, 1997), reflecting similar intracellular processing of FGF2 in the different organs. In a recent in vitro study, we found two novel transitory catabolic fragments of the internalized FGF2 of 14 and 7 kDa (Colin et al, 1997), which could be the results of a very specific event or events in the intracellular processing of FGF2.…”

“…5B). The fragments resulting from the in vivo catabolism of 14 C-FGF2 were then compared with those previously described for the in vitro catabolism of this growth factor by RPE cells (Malecaze et al, 1993;Colin et al, 1997). It seems that the in vivo and in vitro catabolism of this growth factor produces similar catabolic fragments (i.e., of 16, 8, and 5.5 kDa) (Fig.…”

Overexpression of vascular endothelial growth factor induces cell transformation in cooperation with fibroblast growth factor 2

“…It has been previously shown by RT ± PCR that normal RCS RPE cells express FGF2 mRNA (Malecaze et al, 1993). We con®rmed by Western blot that they were actively transcribed.…”

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

“…In culture, RPE cells produce FGF1 and FGF2 (Chen et al, 1996), FGF high a nity receptors (FGFR) and in particular FGFR1 (Guillonneau et al, 1997). In growing RPE cells, ERKs are rapidly and transiently activated in response to exogenous FGFs (Malecaze et al, 1993). We have shown that FGF2 stimulated the production of endogenous FGF1 (Guillonneau et al, 1997) and that high-level expression of endogenous FGF1 is correlated with a reduction in apoptosis during RPE cell aging (Guillonneau et al, 1998b).…”