Axonsextendsignificantdistancestoinnervatetargettissues.Atthesiteofinnervation,targettissuesreleaseneurotrophinsincludingNGF,BDNFandneurotrophin-3thatstimulatethesurvivaloftheassociatedneuron.LocalsignalingbyactivatedTrkreceptorsatthesynapticterminusmediatessomepresynapticneuronalresponsestoneurotrophins.MapkinasepathwaysactivatedbyTrkreceptoractivateErk1andErk2attheterminusstimulatingaxonalgrowth,andPI3KactivatesAKTintheterminusaswell.Activationofthesekinasesdoesnotpropagateasignaltothecellbodythoughanddoesnotinduceatranscriptionalresponse.Thislocalsignalingattheterminusorlocalsignalingatthecellbodyappearsdistinctfromthesignalingpathwaythattransducesthesurvivalsignalfromthetargettissue.Retrogradeaxonaltransportplaysanessentialroleinneuronalsurvivalinducedbyneurotrophinsreleasedatthetargettissue.Failureofretrogradeneurotrophinsignalingmayplayaroleinneurodegenerativeconditions.TheneuronalsurvivalsignalisinitiatedbybindingofneurotrophinstoTrkreceptorsinthepresynapticmembrane,thentravelsbackalongtheaxontotheneuronalcellbody.Totransmitthesignalbackalongtheaxon,activatedTrkreceptorsareinternalizedthroughreceptor-mediatedendocytosisandreceptorcontainingvesiclesthenrapidlytravelbacktothecellbodyalongaxonalmicrotubules.Severalreportsindicatethatneurotrophinsremainreceptor-boundduringtheretrogradeaxonaltransporttothecellbody,butrecentlyitwasreportedthatretrogradetransportofNGFwasnotrequiredtoinduceneuronalsurvival.Onceinthecellbody,Trkreceptorsactivatemultiplepathways.AkeypathwayactivatedbyTrkafterretrogradetransportinvolvesErk5,alsocalledBMK1.TrkactivatesMek5,whichactivatesErk5,inducingphosphorylationoftheCREBandMef2transcriptionfactors.Erk5doesnotdirectlyphosphorylateCREB,buttranslocatesintothenucleusandphosphorylatesthekinaseRsk,whichphosphorylatesCREBinturn.BothCREBandMef2induceatranscriptionalprogramthatcontributestoneuronalsurvival.LocalactivationofErk5onthecellbodydoesnotappeartoinducethesamesignalingsystemorneuronalsurvival,indicatingthattheretrogradetransportisanessentialpartofthesurvivalsignalingsystem.Also,activationofErk1andErk2inthecellbodycaninduceCREBactivationandneuronalsurvival,butthesekinasesarenotactivatedbyneurotrophinsappliedtotheaxonalterminus.AnotherpathwayactivatedbyretrogradeneurotrophinsignalingthoughErk5isPI3Kinase.

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REFERENCES:BarkerPA,HussainNK,McPhersonPS.Retrogradesignalingbytheneurotrophinsfollowsawell-worntrk.TrendsNeurosci.2002Aug;25(8):379-81.BrunetA,DattaSR,GreenbergME.Transcription-dependentand-independentcontrolofneuronalsurvivalbythePI3K-Aktsignalingpathway.CurrOpinNeurobiol.2001Jun;11(3):297-305.Review.Cavanaugh,J.Eetal.(2001)Differentialregulationofmitogen-activatedproteinkinasesERK1/2andERK5byneurotrophins,neuronalactivity,andcAMPinneurons.J.Neurosci.21(2),434-43Finkbeiner,S.(2000)CREBcouplesneurotrophinsignalstosurvivalmessages.Neuron25(1),11-4Heerssen,H.M.,Segal,R.A.(2002)Location,location,location:aspatialviewofneurotrophinsignaltransduction.TrendsNeurosci.25(3),160-5MacInnis,B.L.,Campenot,R.B.(2002)Retrogradesupportofneuronalsurvivalwithoutretrogradetransportofnervegrowthfactor.Science295(5559),1536-9MaclnnisB.,L.,andCampenot,R.,B.Retrogradesupportofneuronalsurvivalwithoutretrogradetransportofnervegrowthfactor.Sciencemagazinefeb222002vol2951536-39Mao,Z.etal.(1999)Neuronalactivity-dependentcellsurvivalmediatedbytranscriptionfactorMEF2.Science286(5440),785-90Watson,F.L.etal.(1999)Rapidnuclearresponsestotarget-derivedneurotrophinsrequireretrogradetransportofligand-receptorcomplex.J.Neurosci.19(18),7889-900Watson,F.L.etal.(2001)NeurotrophinsusetheErk5pathwaytomediatearetrogradesurvivalresponse.Nat.Neurosci.4(10),981-8

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