Journal
DEVELOPMENT
Volume 135, Issue 6, Pages 1039-1047Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.017061
Keywords
heparan sulfate proteoglycans; HSPG; glycosaminoglycan; GAG; bone morphogenetic protein signaling; Drosophila embryonic patterning; decapentaplegic; Dpp; hedgehog; wingless
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Funding
- NCI NIH HHS [P30 CA062203] Funding Source: Medline
- NICHD NIH HHS [T32 HD-007029, T32 HD007029] Funding Source: Medline
- NIGMS NIH HHS [R01 GM071476-04, R01 GM071476, R01 GM055442-09, R01 GM067247-08, GM067247, R01 GM067247, GM5442] Funding Source: Medline
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Heparan sulfate proteoglycans (HSPGs) are extracellular macromolecules found on virtually every cell type in eumetazoans. HSPGs are composed of a core protein covalently linked to glycosaminoglycan (GAG) sugar chains that bind and modulate the signaling efficiency of many ligands, including Hedgehog (Hh), Wingless (Wg) and Bone morphogenetic proteins (BMPs). Here, we show that, in Drosophila, loss of HSPGs differentially affects embryonic Hh, Wg and BMP signaling. We find that a stage-specific block to GAG synthesis prevents HSPG expression during establishment of the BMP activity gradient that is crucial for dorsal embryonic patterning. Subsequently, GAG synthesis is initiated coincident with the onset of Hh and Wg signaling which require HSPGs. This temporal regulation is achieved by the translational control of HSPG synthetic enzymes through internal ribosome entry sites (IRESs). IRES-like features are conserved in GAG enzyme transcripts from diverse organisms, suggesting that this represents a novel evolutionarily conserved mechanism for regulating GAG synthesis and modulating growth factor activity.
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