Abrogation of heparan sulfate synthesis in Drosophila disrupts the Wingless, Hedgehog and Decapentaplegic signaling pathways

Development. 2004 May;131(9):1927-38. doi: 10.1242/dev.01061. Epub 2004 Mar 31.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Disaccharides / chemistry
  • Disaccharides / metabolism
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / anatomy & histology
  • Drosophila melanogaster / physiology*
  • Embryonic Structures / anatomy & histology
  • Embryonic Structures / physiology
  • Exostoses, Multiple Hereditary / genetics
  • Female
  • Gene Expression Regulation, Developmental
  • Hedgehog Proteins
  • Heparitin Sulfate / biosynthesis*
  • Humans
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Molecular Sequence Data
  • Morphogenesis
  • N-Acetylglucosaminyltransferases / genetics
  • N-Acetylglucosaminyltransferases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Sequence Alignment
  • Signal Transduction / physiology*
  • Wings, Animal / anatomy & histology
  • Wings, Animal / physiology
  • Wnt1 Protein

Substances

  • Disaccharides
  • Drosophila Proteins
  • Hedgehog Proteins
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • TTV protein, Drosophila
  • Wnt1 Protein
  • dpp protein, Drosophila
  • wg protein, Drosophila
  • hh protein, Drosophila
  • Heparitin Sulfate
  • N-Acetylglucosaminyltransferases
  • Sotv protein, Drosophila