| A targeted glycan-related gene screen reveals heparan sulfate proteoglycan sulfation regulates WNT and BMP trans-synaptic signaling. | |
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MedLine Citation:
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PMID: 23144627 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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A Drosophila transgenic RNAi screen targeting the glycan genome, including all N/O/GAG-glycan biosynthesis/modification enzymes and glycan-binding lectins, was conducted to discover novel glycan functions in synaptogenesis. As proof-of-product, we characterized functionally paired heparan sulfate (HS) 6-O-sulfotransferase (hs6st) and sulfatase (sulf1), which bidirectionally control HS proteoglycan (HSPG) sulfation. RNAi knockdown of hs6st and sulf1 causes opposite effects on functional synapse development, with decreased (hs6st) and increased (sulf1) neurotransmission strength confirmed in null mutants. HSPG co-receptors for WNT and BMP intercellular signaling, Dally-like Protein and Syndecan, are differentially misregulated in the synaptomatrix of these mutants. Consistently, hs6st and sulf1 nulls differentially elevate both WNT (Wingless; Wg) and BMP (Glass Bottom Boat; Gbb) ligand abundance in the synaptomatrix. Anterograde Wg signaling via Wg receptor dFrizzled2 C-terminus nuclear import and retrograde Gbb signaling via synaptic MAD phosphorylation and nuclear import are differentially activated in hs6st and sulf1 mutants. Consequently, transcriptional control of presynaptic glutamate release machinery and postsynaptic glutamate receptors is bidirectionally altered in hs6st and sulf1 mutants, explaining the bidirectional change in synaptic functional strength. Genetic correction of the altered WNT/BMP signaling restores normal synaptic development in both mutant conditions, proving that altered trans-synaptic signaling causes functional differentiation defects. |
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Authors:
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Neil Dani; Minyeop Nahm; Seungbok Lee; Kendal Broadie |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2012-11-08 |
Journal Detail:
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Title: PLoS genetics Volume: 8 ISSN: 1553-7404 ISO Abbreviation: PLoS Genet. Publication Date: 2012 |
Date Detail:
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Created Date: 2012-11-12 Completed Date: 2013-05-13 Revised Date: 2013-06-13 |
Medline Journal Info:
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Nlm Unique ID: 101239074 Medline TA: PLoS Genet Country: United States |
Other Details:
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Languages: eng Pagination: e1003031 Citation Subset: IM |
Affiliation:
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Department of Biological Sciences and Department of Cell and Developmental Biology, Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee, United States of America. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Animals, Genetically Modified Bone Morphogenetic Proteins / metabolism* Drosophila Proteins / genetics* Drosophila melanogaster / enzymology, genetics, growth & development Gene Expression Regulation, Developmental Genetic Therapy Heparitin Sulfate / metabolism Polysaccharides / metabolism Proteoglycans / metabolism Signal Transduction Sulfatases / genetics* Sulfotransferases / genetics* Synapses* / enzymology, genetics, pathology Synaptic Transmission / genetics Wnt Signaling Pathway* |
| Grant Support | |
ID/Acronym/Agency:
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R01 GM54544/GM/NIGMS NIH HHS; R01 MH084989/MH/NIMH NIH HHS; R01 MH096832/MH/NIMH NIH HHS; R01 MH096832/MH/NIMH NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Bone Morphogenetic Proteins; 0/Drosophila Proteins; 0/Polysaccharides; 0/Proteoglycans; 9050-30-0/Heparitin Sulfate; EC 2.8.2.-/Sulfotransferases; EC 2.8.2.-/heparan sulfate 6-O-sulfotransferase; EC 3.1.6.-/SULF1 protein, Drosophila; EC 3.1.6.-/Sulfatases |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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