A translational block to HSPG synthesis permits BMP signaling in the early Drosophila embryo.
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.
Bornemann
Douglas J
DJ
Developmental and Cell Biology and Developmental Biology Center, University of California Irvine, Irvine, CA, USA.
Park
Sangbin
S
Phin
Sopheap
S
Warrior
Rahul
R
D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D019521:Body Patterning / Q000187:drug effects; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004330:Drosophila / Q000187:drug effects / Q000196:embryology* / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D017344:Genes, Insect; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000096:biosynthesis*; D006493:Heparin / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051155:Wnt1 Protein
D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D019485:Bone Morphogenetic Proteins; D017931:DNA Primers; D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D019812:Heparan Sulfate Proteoglycans; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C113073:TTV protein, Drosophila; D051155:Wnt1 Protein; C074622:wg protein, Drosophila; C077245:hh protein, Drosophila; D006493:Heparin