Shifted, the Drosophila ortholog of Wnt inhibitory factor-1, controls the distribution and movement of Hedgehog.
We here identify and characterize an extracellular modulator of Hedgehog signaling in Drosophila, Shifted. Shifted is required for high levels of long-range signaling in the developing wing imaginal disc. Surprisingly, shifted encodes the only Drosophila ortholog of the secreted vertebrate protein Wnt Inhibitory Factor-1 (WIF-1), whose known role is to bind to extracellular Wnts and inhibit their activity. However, Shifted does not regulate Hedgehog signaling by affecting Wingless or Wnt signaling. We show instead that Shifted is a secreted protein that acts over a long distance and is required for the normal accumulation of Hh protein and its movement in the wing. Our data further indicate that Shf interacts with Hh and the heparan sulfate proteoglycans. Therefore, we propose that Shf stabilizes the interaction between Hh and the proteoglycans, an unexpected role for a member of the WIF-1 family.
Glise
Bruno
B
Centre de Biologie du Développement, UMR 5547 and IFR 109 CNRS/UPS, 118 route de Narbonne, 31062 Toulouse cedex 4, France. glise@cict.fr
Miller
Catherine A
CA
Crozatier
Michèle
M
Halbisen
Michael A
MA
Wise
Steve
S
Olson
David J
DJ
Vincent
Alain
A
Blair
Seth S
SS
D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism; D004330:Drosophila / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D005260:Female; D053823:Hedgehog Proteins; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D008297:Male; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014921:Wings, Animal / Q000254:growth & development / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D019812:Heparan Sulfate Proteoglycans; D012097:Repressor Proteins; C485569:WIF1 protein, human; C077245:hh protein, Drosophila; D002784:Cholesterol