The expression of fibroblast growth factor (FGF) 1, a potent neurotrophic factor, increases during differentiation and remains high in adult neuronal tissues. To examine the importance of this expression on the neuronal phenotype, we have used PC12 cells, a model to study FGF-induced neuronal differentiation. After demonstrating that FGF1 and FGF2 are synthesized by PC12 cells, we investigated if FGF1 expression could be a key element in differentiation. Using the cell signaling pathway to determine the effects of FGF1 alone, FGF1 plus heparin, or a mutated FGF1, we showed an activation to the same extent of mitogen-activated protein (MAP) kinase kinase and MAP kinase (extracellular regulated kinase 1). However, only FGF1 plus heparin could promote PC12 cell differentiation. Thus, the MAP kinase pathway is insufficient to promote differentiation. Analysis of the PC12 cells after the addition of FGF1 plus heparin or FGF2 demonstrated a significant increase in the level of FGF1 expression with the same time course as the appearance of the neuritic extensions. Transfection experiments were performed to enhance constitutivly or after dexamethasone induction the level of FGF1 expression. The degree of differentiation achieved by the cells correlated directly with the amount of FGF1 expressed. The MAP kinase pathway did not appear to be involved. Interestingly, a 5-fold increase in FGF1 in constitutive transfected cells extended dramatically their survival in serum-free medium, suggesting that the rise of FGF1 synthesis during neuronal differentiation is probably linked to their ability to survive in the adult. All of these data demonstrate that, in contrast to the MAP kinase cascade, FGF1 expression is sufficient to induce in PC12 cells both differentiation and survival. It also shows that auto-and trans-activation of FGF1 expression is involved in the differentiation process stimulated by exogenous FGFs through a new pathway which remains to be characterized.
FGF11 and 2 are widely distributed in the peripheral and central nervous systems in the adult. In rat brain, FGF2 is present in most neurons within the cerebral cortex (1), hippocampus (2), and cerebellum (3). High levels of FGF1 expression have been observed in motor neurons, primary sensory neurons, and retinal ganglion neurons (4, 5). In chick brain, the expression of FGF1 is developmentally regulated (6). In bovine and rat embryonic retina, all neuronal layers express FGF1 with an appearance corresponding to their sequential differentiation (7, 8). In rat, the level of FGF1 expression remains uniformly low throughout the embryonic period until postnatal day 7. Thereafter, it increases rapidly, reaching a maximum in the adult retina. In the intermediate central nervous system, subclasses of FGF receptors appear to be down-regulated during development (9), and during retinal embryonic development, the expression of FGFR1 and FGFR2 follows the retinal layering (10). These patterns of FGF expression suggest that these growth factors are involved in the integrit...