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Alternate FGF2-ERK1/2 signaling pathways in retinal photoreceptor and glial cells in vitro
1Laboratoire de Physiopathologie Cellulaire et Moléculaire de la Rétine, INSERM-Université Louis Pasteur EMI 9918, Clinique Médicale A, Centre Hospitalier Régional Universitaire, BP. 426, 1 Place de l'Hôpital, 67091 Strasbourg Cedex, France.
Abstract:
Basic fibroblast growth factor (FGF2) stimulates photoreceptor survival in vivo and in vitro, but the molecular signaling mechanism(s) involved are unknown. Immunohistochemical and immunoblotting analyses of pure photoreceptors, inner retinal neurons, and Müller glial cells (MGC) in vitro revealed differential expression of the high affinity FGF receptors (FGFR1-4), as well as many cytoplasmic signaling intermediates known to mediate the extracellular signal-regulated kinase (ERK1/2) pathway. FGF2-induced tyrosine phosphorylation in vitro exhibited distinct profiles for each culture type, and FGF2-induced ERK1/2 activation was observed for all three preparations. Whereas U0126, a specific inhibitor of ERK kinase (MEK), completely abolished FGF2-induced ERK1/2 tyrosine phosphorylation and survival in cultured photoreceptors, persistent ERK1/2 phosphorylation was observed in cultured inner retinal cells and MGC. Furthermore U0126 treatment entirely blocked nerve growth factor-induced ERK1/2 activation in MGC, as well as FGF2-induced ERK1/2 activation in cerebral glial cells. Taken together, these data indicate that FGF2-induced ERK1/2 activation is entirely mediated by MEK within photoreceptors, which is responsible for FGF2-stimulated photoreceptor survival. In contrast, inner retina/glia possess alternative, cell type, and growth factor-specific MEK-independent ERK1/2 activation pathways. Hence signaling and biological effects elicited by FGF2 within retina are mediated by cell type-specific pathways.
Insights
Basic fibroblast growth factor (FGF2) promotes photoreceptor survival through a MEK-dependent pathway. Other retinal cells utilize distinct, MEK-independent signaling routes for FGF2 effects.
Area of Science:
- Cellular and Molecular Biology
- Neuroscience
- Ophthalmology
Background:
- Basic fibroblast growth factor (FGF2) is known to support photoreceptor survival.
- The precise molecular mechanisms underlying FGF2's effects on retinal cells remain largely uncharacterized.
- Understanding these pathways is crucial for developing therapies for retinal degenerative diseases.
Purpose of the Study:
- To elucidate the molecular signaling pathways by which FGF2 influences photoreceptor survival.
- To investigate the differential activation of the extracellular signal-regulated kinase (ERK1/2) pathway in various retinal cell types.
- To identify cell type-specific signaling mechanisms mediating FGF2's biological effects in the retina.
Main Methods:
- Immunohistochemistry and immunoblotting were used to analyze FGF receptor (FGFR1-4) and signaling intermediate expression in photoreceptors, inner retinal neurons, and Müller glial cells (MGC).
- FGF2-induced tyrosine phosphorylation and ERK1/2 activation were assessed in these cell types.
- The specific MEK inhibitor U0126 was employed to determine the role of the MEK/ERK pathway in FGF2 signaling and photoreceptor survival.
Main Results:
- Photoreceptors, inner retinal neurons, and MGC expressed various FGFRs and ERK1/2 pathway components.
- FGF2 induced distinct tyrosine phosphorylation profiles and ERK1/2 activation across the different cell types.
- In photoreceptors, FGF2-induced survival and ERK1/2 activation were completely dependent on MEK.
- Inner retinal cells and MGC exhibited MEK-independent ERK1/2 activation pathways for FGF2 and nerve growth factor.
Conclusions:
- FGF2-stimulated photoreceptor survival is critically mediated by the MEK/ERK signaling pathway.
- Retinal cells, including inner retinal neurons and glia, employ distinct, cell type-specific MEK-independent pathways for FGF2 signaling.
- These findings highlight the complexity of FGF2 signaling in the retina, with pathway activation tailored to specific cell types.
