Specific and flexible roles of heparan sulfate modifications in Drosophila FGF signaling.
Specific sulfation sequence of heparan sulfate (HS) contributes to the selective interaction between HS and various proteins in vitro. To clarify the in vivo importance of HS fine structures, we characterized the functions of the Drosophila HS 2-O and 6-O sulfotransferase (Hs2st and Hs6st) genes in FGF-mediated tracheal formation. We found that mutations in Hs2st or Hs6st had unexpectedly little effect on tracheal morphogenesis. Structural analysis of mutant HS revealed not only a loss of corresponding sulfation, but also a compensatory increase of sulfation at other positions, which maintains the level of HS total charge. The restricted phenotypes of Hsst mutants are ascribed to this compensation because FGF signaling is strongly disrupted by Hs2st; Hs6st double mutation, or by overexpression of 6-O sulfatase, an extracellular enzyme which removes 6-O sulfate groups without increasing 2-O sulfation. These findings suggest that the overall sulfation level is more important than strictly defined HS fine structures for FGF signaling in some developmental contexts.
Kamimura
Keisuke
K
Department of Genetics, Cell Biology, and Development, The University of Minnesota, Minneapolis, MN 55455, USA.
Koyama
Takashi
T
Habuchi
Hiroko
H
Ueda
Ryu
R
Masu
Masayuki
M
Kimata
Koji
K
Nakato
Hiroshi
H
D000818:Animals; D004331:Drosophila melanogaster / Q000196:embryology* / Q000235:genetics / Q000378:metabolism; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006497:Heparan Sulfate / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D038081:Organogenesis / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism*; D013463:Sulfuric Acid Esters / Q000378:metabolism; D014132:Trachea / Q000166:cytology / Q000196:embryology* / Q000378:metabolism
D005346:Fibroblast Growth Factors; D006497:Heparan Sulfate; D015238:Sulfotransferases; D013463:Sulfuric Acid Esters; C404189:heparan sulfate 6-O-sulfotransferase; C106358:heparan-sulfate 2-sulfotransferase