The Role of Drosophila Heparan Sulfate 6-O-Endosulfatase in Sulfation Compensation |
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Authors: | Katsufumi Dejima Adam Kleinschmit Masahiko Takemura Pui Yee Choi Akiko Kinoshita-Toyoda Hidenao Toyoda Hiroshi Nakato |
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Affiliation: | From the ‡Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota 55455 and ;the §Faculty of Pharmaceutical Sciences, Ritsumeikan University, Shiga 525-8577, Japan |
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Abstract: | The biosynthesis of heparan sulfate proteoglycans is tightly regulated by multiple feedback mechanisms, which support robust developmental systems. One of the regulatory network systems controlling heparan sulfate (HS) biosynthesis is sulfation compensation. A previous study using Drosophila HS 2-O- and 6-O-sulfotransferase (Hs2st and Hs6st) mutants showed that loss of sulfation at one position is compensated by increased sulfation at other positions, supporting normal FGF signaling. Here, we show that HS sulfation compensation rescues both Decapentaplegic and Wingless signaling, suggesting a universal role of this regulatory system in multiple pathways in Drosophila. Furthermore, we identified Sulf1, extracellular HS 6-O-endosulfatase, as a novel component of HS sulfation compensation. Simultaneous loss of Hs2st and Sulf1 led to 6-O-oversulfation, leading to patterning defects, overgrowth, and lethality. These phenotypes are caused at least partly by abnormal up-regulation of Hedgehog signaling. Thus, sulfation compensation depends on the coordinated activities of Hs2st, Hs6st, and Sulf1. |
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Keywords: | Bone Morphogenetic Protein Drosophila Hedgehog Heparan Sulfate Wingless Sulf1 Sulfation Compensation |
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