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[FGF and physiopathological implications]
F Mascarelli1, A Torriglia, G Soubrane
1Unité de Rercherches Gérontologiques, INSERM U118, Paris.
Abstract:
The role of FGF in retinal pathologies can be considered in two respects: 1-as a causative agent (for instance, stimulating aberrant growth or abnormally affecting some aspects of cellular behaviour), or 2-as a possible therapeutic drug (for instance, its ability to rescue neuronal cells from programmed or surgically-induced death), there is evidence for both: the retina, particularly the photoreceptors (PR), seems to be highly succeptible to a host of genetic defects, for instance, in the rat mutant RCS a defect in the pigmented epithelial cells (RPE) leads to the destruction of the PR. Transocular injection of FGF into RCS rats reduces the rate of PR cell loss. On the other hand, we have recently identify a difference in FGF-Receptor cell biology in the RCS mutant which may underline this particular dystrophy. Cultures of purified RPE cells were established from the dystrophic RCS rat and its congenic normal sighted control, and the number and affinity of cell surface FGF-R determined by incubation with 125I-bFGF. Scatchard analysis of the bining data indicated that whereas affinites were in both strains around 60pM, there was a large reduction in receptor number, about 70% in the mutant. Analysis of other FGF/FGF-R criteria, such as mitogenic activity, receptor molecular weight and the profile of FGF degradatoin showed no significant differences between the strains. Thus, defects in the FGF/FGF-R regulating system may actually led to retinal degeneration (RCS rat). But, once again, the underlying principles of FGF mechanisms of action in vivo are at present too incompletely understood to permit rationalization of these various observations.
Insights
Fibroblast Growth Factor (FGF) plays a dual role in retinal diseases, acting as both a cause and potential therapy. Research shows FGF signaling defects contribute to retinal degeneration in RCS rats, impacting photoreceptor survival.
Area of Science:
- Ophthalmology and Vision Science
- Cell Biology
- Molecular Genetics
Context:
- Retinal pathologies, particularly those affecting photoreceptors (PR), are often linked to genetic defects.
- The Royal College of Surgeons (RCS) rat model exhibits retinal degeneration due to a defect in retinal pigment epithelial (RPE) cells.
- Fibroblast Growth Factor (FGF) has a demonstrated dual role in retinal conditions, acting as both a potential causative agent and a therapeutic agent.
Purpose:
- To investigate the role of FGF signaling in the pathogenesis of retinal degeneration in the RCS rat model.
- To compare FGF receptor (FGF-R) characteristics in dystrophic RCS rats versus normal sighted controls.
- To elucidate the underlying molecular mechanisms of FGF action in retinal health and disease.
Summary:
- Studies on RCS rats revealed that transocular injection of FGF can reduce photoreceptor cell loss, highlighting its neuroprotective potential.
- Analysis of purified RPE cells from RCS rats showed a significant reduction (approximately 70%) in cell surface FGF receptor number compared to controls, with similar affinities.
- Defects in the FGF/FGF-R regulatory system are implicated as a potential cause of retinal degeneration in the RCS rat model, although in vivo mechanisms remain incompletely understood.
Impact:
- Identifies a specific molecular defect in FGF receptor expression contributing to retinal dystrophy.
- Provides a basis for exploring FGF-based therapeutic strategies for inherited retinal degenerations.
- Underscores the need for further research into the complex in vivo mechanisms of FGF signaling in the retina.