THE NEUROTROPHIC ACTIVITY OF FIBROBLAST-GROWTH-FACTOR-1 (FGF1) DEPENDS ON ENDOGENOUS FGF1 EXPRESSION AND IS INDEPENDENT OF THE MITOGEN-ACTIVATED PROTEIN-KINASE CASCADE PATHWAY

The expression of fibroblast growth factor (FGF) 1, a potent neurotrop hic 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-ind uced neuronal differentiation. After demonstrating that FGF1 and FGF2 are synthesized by PC12 cells, we investigated if FGF1 expression coul d be a key element in differentiation. Using the cell signaling pathwa y to determine the effects of FGF1 alone, FGF1 plus heparin, or a muta ted FGF1, we showed an activation to the same extent of mitogen-activa ted protein (MAP) kinase kinase and MAP kinase (extracellular regulate d kinase 1). However, only FGF1 plus heparin could promote PC12 cell d ifferentiation. Thus, the MAP kinase pathway is insufficient to promot e differentiation. Analysis of the PC12 cells after the addition of FG F1 plus heparin or FGF2 demonstrated a significant increase in the lev el of FGF1 expression with the same time course as the appearance of t he neuritic extensions. Transfection experiments were performed to enh ance constitutivly or after dexamethasone induction the level of FGF1 expression. The degree of differentiation achieved by the cells correl ated directly with the amount of FGF1 expressed. The MAP kinase pathwa y did not appear to be involved. Interestingly, a 5-fold increase in F GF1 in constitutive transfected cells extended dramatically their surv ival 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 different iation process stimulated by exogenous FGFs through a new pathway whic h remains to be characterized.