THE FIBROBLAST GROWTH-FACTOR RECEPTOR-1 IS NECESSARY FOR THE INDUCTION OF NEURITE OUTGROWTH IN PC12 CELLS BY AFGF

The PC12 subclone, fnr-PC12 cells, is defective in neurite outgrowth i n response to acidic fibroblast growth factor (aFGF); however, its res ponse to nerve growth factor (NGF) is normal. Examination of the expre ssion of FGF receptors (FGFRs) revealed that although PC12 cells expre ss FGFR-1, -3, and -4, fnr-PC12 cells have a reduced level of expressi on of FGFR-1 but not FGFR-3 and -4. Transfection of FGFR-1 into fnr-PC 12 cells efficiently restored aFGF-induced neurite outgrowth, whereas transfection of FGFR-3 was much less efficient. Transfection of a chim eric receptor consisting of the extracellular domain of FGFR-3 fused t o the transmembrane and intracellular domain of FGFR-1, termed FR31b, efficiently restored aFGF-induced neurite outgrowth. This demonstrates that the difference between these two receptors in their ability to i nduce neurite outgrowth is attributable to differences in the signalin g capacity of their cytoplasmic domains. Activation of the chimeric re ceptor by aFGF induced a stronger and more persistent increase in the tyrosine phosphorylation of cellular proteins than did activation of F GFR-3 alone. In particular, the activation of MAP kinase by fR31b was more persistent than when activated by FGFR-3. This difference in sign aling potential of FGFR-1 and -3 in fnr-PC12 cells may account for the difference in the potential for induction of neurite outgrowth. These results demonstrate that FGF-induced neurite outgrowth in PC12 cells occurs mainly via FGFR-1 and not via the other FGFRs expressed in thes e cells.