A Targeted Glycan-Related Gene Screen Reveals Heparan Sulfate Proteoglycan Sulfation Regulates WNT and BMP Trans-Synaptic Signaling 英文参考文献.docVIP

ATargetedGlycan-RelatedGeneScreenRevealsHeparan SulfateProteoglycanSulfationRegulatesWNTandBMP Trans-SynapticSignaling NeilDani1,MinyeopNahm2,SeungbokLee2,KendalBroadie1* 1DepartmentofBiologicalSciencesandDepartmentofCellandDevelopmentalBiology,KennedyCenterforResearchonHumanDevelopment,VanderbiltUniversity, Nashville,Tennessee,UnitedStatesofAmerica,2DepartmentofCellandDevelopmentalBiology,SeoulNationalUniversity,Seoul,RepublicofKorea Abstract ADrosophilatransgenicRNAiscreentargetingtheglycangenome,includingallN/O/GAG-glycanbiosynthesis/modification enzymes and glycan-binding lectins, was conducted to discover novel glycan functions in synaptogenesis. As proof-of- product,wecharacterizedfunctionallypairedheparansulfate(HS)6-O-sulfotransferase(hs6st)andsulfatase(sulf1 ),which bidirectionally control HS proteoglycan (HSPG) sulfation. RNAi knockdown of hs6st and sulf1 causes opposite effects on functionalsynapsedevelopment,withdecreased(hs6st)andincreased(sulf1)neurotransmissionstrengthconfirmedinnull 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)andBMP(GlassBottomBoat;Gbb)ligandabundanceinthesynaptomatrix.AnterogradeWgsignalingvia Wg receptor dFrizzled2 C-terminus nuclear import and retrograde Gbb signaling via synaptic MAD phosphorylation and nuclearimportaredifferentiallyactivatedinhs6standsulf1mutants.Consequently,transcriptionalcontrolofpresynaptic glutamate release machinery and postsynaptic glutamate receptors is bidirectionally altered in hs6st and sulf1 mutants, explainingthebidirectionalchangeinsynapticfunctionalstrength.GeneticcorrectionofthealteredWNT/BMPsignaling restores normal synaptic development in both mutant conditions, proving that altered trans-synaptic signaling causes functionaldifferentiationdefects. Citation:DaniN,NahmM,LeeS,BroadieK(2012