AN ALTERNATIVELY SPLICED FIBROBLAST-GROWTH-FACTOR (FGF)-5 MESSENGER-RNA IS ABUNDANT IN BRAIN AND TRANSLATES INTO A PARTIAL AGONIST ANTAGONIST FOR FGF-5 NEUROTROPHIC ACTIVITY/

We detected in the brain and then cloned two novel, short forms of hum an and mouse fibroblast growth factor (FGF)-5 mRNA, which were designa ted human FGF-5S (hFGF-5S) and mouse FGF-5S (mFGF-5S), respectively. G enomic analysis indicated that mFGF-5S and authentic mFGF-5 mRNAs were transcribed from a single gene; hFGF-5S and mFGF-5S mRNAs were genera ted by excluding the second exon of the respective FGF-5 genes, and th e alternatively spliced mRNAs encoded for 123- and 121-amino acid prot eins, respectively. Indeed, a neuron-like cell line expressing mFGF-5S mRNA secreted a protein of the expected size and with FGF-5 antigenic ity. In PC12 cells, expression of hFGF-5 or exposure to hFGF-5 protein induced differentiation. Neither expression of hFGF-5S, alone, nor co -expression of hFGF-5S with hFGF-5 induced significant differentiation , At high concentrations, hFGF-5S protein partially antagonized FGF-5 activity, whereas by itself, hFGF-5S exerted very weak neurotrophic ac tivity. hFGF-5S protein binds to FGF receptor (FGFR)-1 on PC12 transfe ctants and partially inhibits hFGF-5-induced tyrosine phosphorylation of FGFR-1 and an FGFR substrate, but it also induces phosphorylation b y itself. These results suggest that FGF-5S is a naturally expressed p artial agonist/antagonist of FGF-5 neurotrophic activity in the brain and that its effects are exerted in part at the level of the receptor.