RESEARCHOpenAccessYthdf2-mediatedm6AmRNAclearancemodulatesneuraldevelopmentinmiceMiaomiaoLi1,2†,XuZhao1,2*†,WeiWang3,HailingShi4,5,QingfeiPan6,ZhikeLu4,5,SoniaPeñaPerez1,RajikalaSuganthan1,ChuanHe4,5,MagnarBjørås1,3*andArneKlungland1,2*AbstractBackground:N6-methyladenosine(m6A)modificationinmRNAswasrecentlyshowntobedynamicallyregulated,indicatingapivotalroleinmultipledevelopmentalprocesses.Mostrecently,itwasshownthattheMettl3-Mettl14writercomplexofthismarkisrequiredforthetemporalcontrolofcorticalneurogenesis.Them6AreaderproteinYthdf2promotesmRNAdegradationbyrecognizingm6AandrecruitingthemRNAdecaymachinery.Results:Weshowthattheconditionaldepletionofthem6AreaderproteinYthdf2inmicecauseslethalityatlateembryonicdevelopmentalstages,withembryoscharacterizedbycompromisedneuraldevelopment.Wedemonstratethatneuralstem/progenitorcell(NSPC)self-renewalandspatiotemporalgenerationofneuronsandothercelltypesareseverelyimpactedbythelossofYthdf2inembryonicneocortex.Combininginvivoandinvitroassays,weshowthattheproliferationanddifferentiationcapabilitiesofNSPCsdecreasesignificantlyinYthdf2−/−embryos.TheYthdf2−/−neuronsareunabletoproducenormallyfunctioningneurites,leadingtofailureinrecoveryuponreactiveoxygenspeciesstimulation.Consistently,expressionofgenesenrichedinneuraldevelopmentpathwaysissignificantlydisturbed.Detailedanalysisofthem6A-methylomesofYthdf2−/−NSPCsidentifiesthattheJAK-STATcascadeinhibitorygenescontributetoneuroprotectionandneuriteoutgrowthsshowincreasedexpressionandm6Aenrichment.InagreementwiththefunctionofYthdf2,delayeddegradationofneurondifferentiation-relatedm6A-containingmRNAsisseeninYthdf2−/−NSPCs.Conclusions:Weshowthatthem6AreaderproteinYthdf2modulatesneuraldevelopmentbypromotingm6A-dependentdegradationofneuraldevelopment-relatedmRNAtargets.Keywords:Ythdf2,N6-methyladenosine(m6A),Neuraldevelopment,Neurogenesis,mRNAclearanceBackgroundOverthepastdecade,morethan100post-transcriptionallymodifiedribonucleotideshavebeenidentifiedinvarioustypesofRNA[1].Mu...
