FGF-8 ISOFORMS ACTIVATE RECEPTOR SPLICE FORMS THAT ARE EXPRESSED IN MESENCHYMAL REGIONS OF MOUSE DEVELOPMENT

The Fgf8 gene is expressed in developing Limb and craniofacial structu res, regions known to be important for growth and patterning of the mo use embryo, Although Fgf8 is alternatively spliced to generate at leas t 7 secreted isoforms that differ only at their mature amino terminus, the biological significance of these multiple isoforms is not known. In this report, we demonstrate that multiple FGF-8 isoforms are presen t at sites of Fgf8 expression during mouse development. To address the possibility that the FGF-8 isoforms might interact with different fib roblast growth factor receptors, we prepared recombinant FGF-8 protein isoforms. We examined the ability of these proteins to activate alter natively spliced forms of fibroblast growth factor receptors 1-3, and fibroblast growth factor receptor 4. Recombinant FGF-8b and FGF-8c act ivate the 'c' splice form of FGFR3, and FGFR4, while FGF-8b also effic iently activates 'c' splice form of FGFR2. No activity could be detect ed for recombinant or cell expressed FGP-8a. Furthermore, none of the isoforms tested interact efficiently with 'b' splice forms of FGFR1-3, or the 'c' splice form of FGFR1, These results indicate that the FGF- 8b and FGF-8c isoforms, produced by ectodermally derived epithelial ce lls, interact with mesenchymally expressed fibroblast growth factor re ceptors, FGF-8b and FGF-8c may therefore provide a mitogenic signal to the underlying mesenchyme during limb and craniofacial development.