Document Detail


A targeted glycan-related gene screen reveals heparan sulfate proteoglycan sulfation regulates WNT and BMP trans-synaptic signaling.
MedLine Citation:
PMID:  23144627     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Neil Dani; Minyeop Nahm; Seungbok Lee; Kendal Broadie
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-11-08
Journal Detail:
Title:  PLoS genetics     Volume:  8     ISSN:  1553-7404     ISO Abbreviation:  PLoS Genet.     Publication Date:  2012  
Date Detail:
Created Date:  2012-11-12     Completed Date:  2013-05-13     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  101239074     Medline TA:  PLoS Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e1003031     Citation Subset:  IM    
Affiliation:
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.
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MeSH Terms
Descriptor/Qualifier:
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:
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:
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

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