FGF-8 is a member of the family of fibroblast growth factors and is expressed during vertebrate embryo development. Eight potential FGF-8 isoforms are generated by alternative splicing in mice, several of which are expressed during embryogenesis in epithelial locations. The significance of the multiple isoforms is currently unknown. In this report, we investigate the expression patterns and the specificity of the FGF-8 isoforms for known fibroblast growth factor (FGF) receptors. RNAs for seven of the eight potential isoforms are present at multiple sites of embryonic Fgf8 expression. None of the FGF-8 isoforms exhibited activity when assayed with BaF3 cells expressing the "b" splice forms of FGF receptors 1-3, which are mostly expressed in epithelial tissues. Mesenchymally expressed "c" splice forms of FGF receptors 2 and 3 and FGF receptor 4 were activated by several FGF-8 isoforms. These findings are consistent with the hypothesis that the multiple FGF-8 isoforms are functionally redundant and function to signal in paracrine (epithelial to mesenchymal) contexts.The mammalian fibroblast growth factor (FGF) 1 family currently consists of structurally related polypeptides encoded by 10 genes (FGF-1-10) (reviewed in Ref. 1;. Four distinct genes code for high affinity transmembrane receptor tyrosine kinases (FGFR1-4) that bind FGF ligands and display varying patterns of expression (reviewed in Ref. 5). Alternative mRNA splicing generates isoforms of receptors 1-3 that exhibit unique ligand binding characteristics (6 -9). FGF receptor activation involves ligand binding and receptor dimerization, followed by transphosphorylation of the receptor and transduction of the signal into a biological response (5). FGF signal transduction has been implicated in development, wound healing, angiogenesis, and tumorigenesis (reviewed in Ref. 1). Germ line mutations of FGFs and FGFRs in mice (10 -15) and humans (16 -21) demonstrate the importance of FGF signaling in the process of development.FGF-8 was first identified as an androgen-induced growth factor secreted by the mouse mammary tumor cell line SC-3 (2). Subsequently, Fgf8 was identified as a Wnt1-cooperating protooncogene in murine mammary tumorigenesis (22). Fgf8 expression has been detected during murine and chicken embryogenesis in regions of outgrowth and patterning, including the primitive epiblast, the apical ectodermal ridge of the limb bud, the primitive streak, the tail bud, the facial primordia, and the midbrain-hindbrain junction (22-29). The murine and human genes encoding FGF-8 have been localized to mouse chromosome 19 and human chromosome 10q24 -26 (25, 26, 30, 31). The murine Fgf8 gene is unusual in the FGF family in that there are four exons (exons 1A-1D) equivalent to the usual exon 1 in other FGF genes (22,25,32). Alternative splicing of the four alternatively spliced exons results in potentially eight protein isoforms that differ at their amino termini and share a common carboxyl terminus encoded by exons 1D, 2, and 3 (22,25,32). Human FGF8 is similar ...

A new member of the fibroblast growth factor (FGF) family, FGF-13, has been molecularly cloned as a result of high throughput sequencing of a human ovarian cancer cell library. The open reading frame of the novel human gene (1419 bp) encodes for a protein of 216 a.a. with a molecular weight of 22 kDa. The FGF-13 sequence contains an amino-terminal hydrophobic region of 23 a.a. characteristic of a signal secretion sequence. FGF-13 is most homologous, 70% similarity at the amino acid level, to FGF-8. Northern hybridization analysis demonstrated prominent expression of FGF-13 in human foetal and adult brain, particularly in the cerebellum and cortex. In proliferation studies with BaF3 cells, FGF-13 preferentially activates cell clones expressing either FGF receptor variant, 3-IIIc or 4. The signal transduction pathways of FGF-13 and FGF-2 were compared in rat hippocampal astrocytes. The two FGFs induce an equivalent level of tyrosine phosphorylation of mitogen-activated protein kinase (MAPK) and c-raf activation. However, FGF-13 is more effective than FGF-2 in inducing the phosphorylation of phospholipase C-gamma (PLC-gamma). Treatment of neuronal cultures from rat embryonic cortex with FGF-13 increases the number of glutamic acid decarboxylase immunopositive neurons, the level of high-affinity gamma-aminobutyric acid (GABA) uptake, and choline acetyltransferase enzyme activity. The GABAergic neuronal response to FGF-13 treatment is rapid with a significant increase occurring within 72 h. We have identified a novel member of the FGF family that is expressed in the central nervous system (CNS) and increases the number as well as the level of phenotypic differentiation of cortical neurons in vitro.