title: Abrogation of heparan sulfate synthesis in Drosophila disrupts the Wingless, Hedgehog and Decapentaplegic signaling pathways.
abstract: Studies in Drosophila and vertebrate systems have demonstrated that heparan sulfate proteoglycans (HSPGs) play crucial roles in modulating growth factor signaling. We have isolated mutations in sister of tout velu (sotv), a gene that encodes a co-polymerase that synthesizes HSPG glycosaminoglycan (GAG) chains. Our phenotypic and biochemical analyses reveal that HS levels are dramatically reduced in the absence of Sotv or its partner co-polymerase Tout velu (Ttv), suggesting that both copolymerases are essential for GAG synthesis. Furthermore, we find that mutations in sotv and ttv impair Hh, Wg and Decapentaplegic (Dpp) signaling. This contrasts with previous studies that suggested loss of ttv compromises only Hh signaling. Our results may contribute to understanding the biological basis of hereditary multiple exostoses (HME), a disease associated with bone overgrowth that results from mutations in EXT1 and EXT2, the human orthologs of ttv and sotv.
authors.affiliation: Developmental and Cell Biology, University of California Irvine, Irvine, CA 92697, USA.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Bornemann
authors.forename: Jason E
authors.initials: JE
authors.lastname: Duncan
authors.forename: William
authors.initials: W
authors.lastname: Staatz
authors.forename: Scott
authors.initials: S
authors.lastname: Selleck
authors.forename: Rahul
authors.initials: R
authors.lastname: Warrior
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004187:Disaccharides / Q000737:chemistry / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000033:anatomy & histology / Q000502:physiology*; D004628:Embryonic Structures / Q000033:anatomy & histology / Q000502:physiology; D005097:Exostoses, Multiple Hereditary / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D006497:Heparan Sulfate / Q000096:biosynthesis*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009024:Morphogenesis; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology*; D014921:Wings, Animal / Q000033:anatomy & histology / Q000502:physiology; D051155:Wnt1 Protein
chemical_list: D004187:Disaccharides; D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D006497:Heparan Sulfate; D008565:Membrane Proteins; D017351:N-Acetylglucosaminyltransferases; D011518:Proto-Oncogene Proteins; D051155:Wnt1 Protein; C113073:TTV protein, Drosophila; C064196:dpp protein, Drosophila; C074622:wg protein, Drosophila; C077245:hh protein, Drosophila; C487133:Sotv protein, Drosophila