title: Three Drosophila EXT genes shape morphogen gradients through synthesis of heparan sulfate proteoglycans.
abstract: The signaling molecules Hedgehog (Hh), Decapentaplegic (Dpp) and Wingless (Wg) function as morphogens and organize wing patterning in Drosophila. In the screen for mutations that alter the morphogen activity, we identified novel mutants of two Drosophila genes, sister of tout-velu (sotv) and brother of tout-velu (botv), and new alleles of tout-velu (ttv). The encoded proteins of these genes belong to an EXT family of proteins that have or are closely related to glycosyltransferase activities required for biosynthesis of heparan sulfate proteoglycans (HSPGs). Mutation in any of these genes impaired biosynthesis of HSPGs in vivo, indicating that, despite their structural similarity, they are not redundant in the HSPG biosynthesis. Protein levels and signaling activities of Hh, Dpp and Wg were reduced in the cells mutant for any of these EXT genes to a various degree, Wg signaling being the least sensitive. Moreover, all three morphogens were accumulated in the front of EXT mutant cells, suggesting that these morphogens require HSPGs to move efficiently. In contrast to previous reports that ttv is involved exclusively in Hh signaling, we found that ttv mutations also affected Dpp and Wg. These data led us to conclude that each of three EXT genes studied contribute to Hh, Dpp and Wg morphogen signaling. We propose that HSPGs facilitate the spreading of morphogens and therefore, function to generate morphogen concentration gradients.
authors.affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Takei
authors.forename: Yutakahiko
authors.initials: Y
authors.lastname: Ozawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Sato
authors.forename: Akira
authors.initials: A
authors.lastname: Watanabe
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tabata
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster / Q000196:embryology* / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D053823:Hedgehog Proteins; D019812:Heparan Sulfate Proteoglycans / Q000096:biosynthesis*; D008297:Male; D008969:Molecular Sequence Data; D009024:Morphogenesis; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D051155:Wnt1 Protein
chemical_list: D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D019812:Heparan Sulfate Proteoglycans; D011518:Proto-Oncogene Proteins; D051155:Wnt1 Protein; C064196:dpp protein, Drosophila; C074622:wg protein, Drosophila; C077245:hh protein, Drosophila