Overlapping Expression and Redundant Activation of Mesenchymal Fibroblast Growth Factor (FGF) Receptors by Alternatively Spliced FGF-8 Ligands

doi:10.1074/jbc.272.6.3733

Overlapping Expression and Redundant Activation of Mesenchymal Fibroblast Growth Factor (FGF) Receptors by Alternatively Spliced FGF-8 Ligands*

From the Departments of ^‡ Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110
Departments of ^| Pathology, Washington University School of Medicine, St. Louis, Missouri 63110 and
Departments of ^§ Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110 and the
** Division of Congenital Defects, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington 98195

^§§ Supported by a March of Dimes Basil O'Connor starter scholar award. To whom correspondence should be addressed:
Dept. of Pediatrics, Washington University School of Medicine, P. O. Box 8116, One Children's Place, St. Louis, MO 63110.
Tel.: 314-454-2547; Fax: 314-454-2685; E-mail: macarthur{at}kids.wustl.edu

Abstract

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.

Footnotes

↵^¶ Supported by a research postdoctoral fellowship for physicians from the Howard Hughes Medical Institute.
↵^‡‡ Supported by a Beckman Foundation young investigator's award.
↵* This work was supported in part by National Institutes of Health Research Grants R01 CA70601 (to C. A. M.), R01 CA60673 (to D. M. O.), and K11 HD-01054 and P03 HD-28834 (to M. L. C.) and by research grants from the Edward Mallinckrodt, Jr., Foundation (to C. A. M.) and the Elsa U. Pardee Foundation (to C. A. M.). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

FGF

fibroblast growth factor

rFGF

recombinant fibroblast growth factor

FGFR

fibroblast growth factor receptor

RT-PCR

reverse transcription-polymerase chain reaction.
- Received September 19, 1996.
- Revision received November 15, 1996.