Abstract
Fibroblast growth factors (FGFs) are secreted regulatory proteins involved in various developmental processes. In vertebrates, the FGF superfamily comprises 22 members. In non-vertebrates, six FGF genes have been identified in Ciona intestinalis, three in Drosophila melanogaster, and two (let-756 and egl-17) in Caenorhabditis elegans. The core of LET-756 shares a 30-50% sequence identity with the various members of the superfamily. The relationships between vertebrate and non-vertebrate FGFs are not clear. We made chimeric FGFs by replacing the core region of LET-756 by the cores of various mammalian, fly, and worm FGFs. LET-756 deleted in its core region was no longer able to rescue the lethal phenotype of a let-756 null mutant, and only chimeras containing the cores of FGFs 9, 16, and 20 showed rescue capacity. This core contains an internal motif of six amino acid residues (EFISIA) whose deletion or mutation abolished both the rescue activity and FGF secretion in the supernatant of transfected COS-1 cells. Chimera containing the core of C. intestinalis FGF9/16/20, a potential ortholog of FGF9 lacking the complete EFISIA motif, was not able to rescue the lethal phenotype or be secreted. However, the introduction of the EFISIA motif restored both activities. The data show that the EFISIA motif in the core of LET-756 is essential for its biological activity and that FGFs 9, 16, and 20, which contain that motif, are functionally close to LET-756 and may be evolutionary related. This non-classical mode of secretion using an internal motif is conserved throughout evolution.
Highlights
Fibroblast growth factors (FGF) are secreted regulatory proteins
To speak only of fully sequenced genomes, three Fgf genes are known in Drosophila melanogaster [4, 5], two in Caenorhabditis elegans [6, 7] and six in the small marine ascidian Ciona intestinalis (8, 9 and our unpublished observations)
From an evolutionary point of view, two striking features are associated with the FGF superfamily
Summary
The FGF superfamily comprises 22 members involved in various developmental processes including formation of mesoderm during gastrulation, patterning during early post-implantation, and development of various tissues such as ear, limb, hair, nervous and skeletal systems [1] This role has been established through series of studies on animal models and identification of human hereditary skeletal disorders that are associated with mutations of the tyrosine kinase FGF receptors (FGFR) [2, 3]. FGFs exert their function by ways independent of the FGFRs [14, 15], group in a separate family This analysis is not conclusive for the non-vertebrate FGFs and does not allow to establish direct phylogenic relationship between human, fly and worm FGFs. To understand the importance of FGF expansion and the phylogenetic and/or functional relationships that may exist between vertebrate and non-vertebrate FGFs, we studied C. elegans LET-756/FGF as a model. The purpose was to assess whether this worm FGF could be related to any particular FGF family despite the limitation of the phylogenetic analysis
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