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 structures, regions known to be important for growth and patterning of the mouse embryo. Although Fgf8 is alternatively spliced to generate at least 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 present at sites of Fgf8 expression during mouse development. To address the possibility that the FGF-8 isoforms might interact with different fibroblast growth factor receptors, we prepared recombinant FGF-8 protein isoforms. We examined the ability of these proteins to activate alternatively spliced forms of fibroblast growth factor receptors 1-3, and fibroblast growth factor receptor 4. Recombinant FGF-8b and FGF-8c activate the 'c' splice form of FGFR3, and FGFR4, while FGF-8b also efficiently activates 'c' splice form of FGFR2. No activity could be detected for recombinant or cell expressed FGF-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 cells, interact with mesenchymally expressed fibroblast growth factor receptors. FGF-8b and FGF-8c may therefore provide a mitogenic signal to the underlying mesenchyme during limb and craniofacial development.
MacArthur
C A
CA
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Lawshé
A
A
Xu
J
J
Santos-Ocampo
S
S
Heikinheimo
M
M
Chellaiah
A T
AT
Ornitz
D M
DM
D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000196:embryology; D005121:Extremities / Q000196:embryology; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D015870:Gene Expression; D006133:Growth Substances / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007536:Isomerism; D008648:Mesoderm / Q000737:chemistry*; D051379:Mice; D008815:Mice, Inbred Strains; D008938:Mitosis / Q000187:drug effects; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000235:genetics; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases; D011869:Radioligand Assay; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins
C496457:Fgf8 protein, mouse; D006133:Growth Substances; D009363:Neoplasm Proteins; D017468:Receptors, Fibroblast Growth Factor; D011994:Recombinant Proteins; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; C496349:Fgfr1 protein, mouse; C496354:Fgfr2 protein, mouse; C496366:Fgfr3 protein, mouse; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3