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.
Highlights
heparan sulfate (HS) sulfation compensation provides robustness to cellular signaling and animal development, but its mechanism is unknown
These results showed that the HS sulfation compensation rescues both Dpp and Wg signaling, suggesting a universal role for this regulatory system in multiple pathways in Drosophila
HS structural analysis showed that HS isolated from Hs2st;Sulf1 double mutants lacks 2-O-sulfation but has a higher level of 6-O-sulfation compared with Hs2st mutants, suggesting that this “oversulfation” of HS led to the severe phenotypes and up-regulated Hh signaling of Hs2st;Sulf1 double mutants. These results show that Sulf1 is involved in fine-tuning of 6-O-sulfation levels, which is required for normal HS sulfation compensation
Summary
HS sulfation compensation provides robustness to cellular signaling and animal development, but its mechanism is unknown. HSPG biosynthesis provides additional layers of fine regulation of cell-cell communication, supporting robust developmental systems Another feedback regulatory network controlling HS biosynthesis involves compensatory increases in sulfation at other positions in response to mutation of a HS sulfotransferase gene. We found that both pathways were basically intact in Hs2st or Hs6st single mutants they were severely impaired in cells deficient for both Hsst genes These results showed that the HS sulfation compensation rescues both Dpp and Wg signaling, suggesting a universal role for this regulatory system in multiple pathways in Drosophila. These results show that Sulf is involved in fine-tuning of 6-O-sulfation levels, which is required for normal HS sulfation compensation
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