title: HSPG synthesis by zebrafish Ext2 and Extl3 is required for Fgf10 signalling during limb development.
abstract: Heparan sulphate proteoglycans (HSPGs) are known to be crucial for signalling by the secreted Wnt, Hedgehog, Bmp and Fgf proteins during invertebrate development. However, relatively little is known about their effect on developmental signalling in vertebrates. Here, we report the analysis of daedalus, a novel zebrafish pectoral fin mutant. Positional cloning identified fgf10 as the gene disrupted in daedalus. We find that fgf10 mutants strongly resemble zebrafish ext2 and extl3 mutants, which encode glycosyltransferases required for heparan sulphate biosynthesis. This suggests that HSPGs are crucial for Fgf10 signalling during limb development. Consistent with this proposal, we observe a strong genetic interaction between fgf10 and extl3 mutants. Furthermore, application of Fgf10 protein can rescue target gene activation in fgf10, but not in ext2 or extl3 mutants. By contrast, application of Fgf4 protein can activate target genes in both ext2 and extl3 mutants, indicating that ext2 and extl3 are differentially required for Fgf10, but not Fgf4, signalling during limb development. This reveals an unexpected specificity of HSPGs in regulating distinct vertebrate Fgfs.
authors.affiliation: European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: William H J
authors.initials: WH
authors.lastname: Norton
authors.forename: Johan
authors.initials: J
authors.lastname: Ledin
authors.forename: Heiner
authors.initials: H
authors.lastname: Grandel
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Neumann
mesh_terms: D000818:Animals; D005121:Extremities / Q000196:embryology*; D051526:Fibroblast Growth Factor 10 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019812:Heparan Sulfate Proteoglycans / Q000096:biosynthesis*; D009154:Mutation; D017351:N-Acetylglucosaminyltransferases / Q000502:physiology*; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000502:physiology; D000099065:Exostosin 2
chemical_list: C484685:Extl3 protein, mouse; D051526:Fibroblast Growth Factor 10; D019812:Heparan Sulfate Proteoglycans; D029961:Zebrafish Proteins; C416220:dackel protein, zebrafish; D017351:N-Acetylglucosaminyltransferases; D000099065:Exostosin 2