The Journal of Biology

JCB

Anthony Brown destined fortheaxonaretransported anterogradely,toward body forthesynthesisofmanytheircomponents.Materials meter inlargeanimals,yettheyaredependentonthecell drical processescanextendfordistancesinexcessofone ofnervecellsistrulyanepicone.Theseslendercylin- In theworldofintracellulartransport,journeyalong Fast andslowaxonaltransport messenger RNAs. polymers, cytosolicproteincomplexes,ribosomes,and tal cle, aswellnonmembranouscargoessuchcytoskele- type ofmembranousorganelleandspeciestransportvesi- are farmorevariedthanpreviouslyimagined,includingevery (Vale andMilligan,2000).Moreover,thecargoesthemselves in aparticulardirectionalongcytoskeletalpolymertracks motor proteinsthatbindspecificcargoesandconveythem transport isorchestratedbyadiverseconstellationofmolecular molecular mechanisms.Wenowknowthatintracellular the extentofthesemovementsinsidecellsandtheirunderlying years wehavewitnessedarevolutioninourunderstandingof of intracellularcomponentsfromplacetoplace.Inrecent plasm, nothingcanfunctionwithouttheconstantshuttling cell. Inthebustlingmacromolecularenvironmentofcyto- Intracellular movementisthelifebloodofeukaryotic Introduction panies www.jcb.org/cgi/content/full/jcb.200212017/DC1) accom- the timethatthey spendmoving. A Flashfeature (http:// diverse cargostructures thatdifferintheproportion of and slow axonaltransport basedonrapid movements of longed pauses. This supportsaunified perspective forfast slow rate isduetorapid movements interrupted by pro- axonal transport isgenerated by fastmotors andthatthe ment ofcytoskeletal polymers inaxonssuggestthatslow transport, respectively. Recentobservations onthemove- along axonsinthefastandslow componentsofaxonal Membranous andnonmembranous cargoesare transported Neurobiotechnology ofNeuroscience, CenterandDepartment The Ohio State University, Columbus,OH43210 cargoes: aunifiedperspective Axonal transport ofmembranous andnonmembranous  E-mail: [email protected] Tel.: (614)292-1205. Fax:(614)292-5379. 43210. OH Columbus, sity, NeurobiotechnologyCenter,Rightmire Hall,1060CarmackRoad, Address correspondencetoDr.Anthony Brown,TheOhioStateUniver- http://www.jcb.org/cgi/doi/10.1083/jcb.200212017 The Journal ofCellBiology

The Rockefeller University Press, 0021-9525 Mini-Review

this Mini-Review. ,

Volume 160, Number 6,March 17,2003817–821 /2003/03/817/5 $8.00 se, butratherthemannerinwhichmovementisregulated. between fastandslowtransportisnottherateofmovementper transported byfastmotorsandthattheprincipledifference these cargoesinlivingcellsnowindicatethattheyareall mechanisms, butdirectobservationsonthemovementof and nonmembranouscargoesmovebyfundamentallydistinct transport haslongbeenassumedtoindicatethatmembranous nents. Thedifferenceintherateoffastandslowaxonal complexesmovemoreslowly,intheslowcompo- axonal transport,whereascytoskeletalpolymersandcytosolic movemostrapidly,inthefastcomponentsof move atdifferentrates(Tytelletal.,1981).Membranous membranous andnonmembranouscargostructuresthat are transportedalongaxonsinassociationwithdistinct digm hasdemonstratedthatproteinsandothermolecules 1980). Severaldecadesofworkusingthisexperimentalpara- using radioisotopicpulselabeling(GrafsteinandForman, of axonaltransportcomesfromstudiesonlaboratoryanimals throughoutthelifeofneuron. aretransportedalongtheentirelengthof cules andmembranouscompartmentsthatcompriseaxonal is remarkableforitsscale:essentiallyallofthemacromole- and membranetrafficthatoccurinalleukaryoticcells,butit mentally differentfromthepathwaysofmacromolecular transport process,knownasaxonaltransport,isnotfunda- ported retrogradely,towardthecellbody.Thisbidirectional the axontip,andmaterialsdestinedtoreturnaretrans- conveying auniquemolecular consignment,andeachthe movement ofadiversefleetorganelles, eachtypeoforganelle of thesecomponentsfastaxonal transportrepresentsthe transport vesiclesmoveanterogradelyatmaximalratesof in itsmembrane,orboundtosurface.Golgi-derived either becausetheyaresequesteredwithinitslumen,embedded association withoneormoresubclassesoforganellevesicle, that movealongtheaxonatfastratesdosobyvirtueoftheir transport. Themanyproteins,,andpolysaccharides Membranous organellesaretheprincipalcargoesoffastaxonal Movement ofmembranousorganelles rates of , andautophagosomes moveretrogradelyatmaximal 200–400 mm/d(or Most ofwhatweknowaboutthecompositionandkinetics 100–250 mm/d(or 2–5 m/s), whereasendocyticvesicles, 1–3 m/s) (TableI).Each 817 The Journal of Cell Biology 818 , organelles move lessrapidlythanmostGolgi-derived and ganelles aremitochondria (Hollenbeck,1996, Fig.1).These ganelles ischaracterizedbyahigh dutyratio. say thattheaxonaltransport ofmanymembranousor- that acargostructurespends actually moving.Thus,wecan tracellular transport,theduty ratioistheproportionoftime efficiency isintermsoftheduty ratio.Inthecontextofin- infrequently duringtheirjourney.Onewaytoexpressthis move alongaxonsinahighlyefficientmanner,pausingonly observations indicatethatmanymembranousorganelles motors invitro(e.g.,WoehlkeandSchliwa,2000).These I) andalsotothemaximalratesreportedformicrotubule transport determinedbyradioisotopicpulselabeling(Table rates thatarecomparabletothemaximalrateoffastaxonal in acontinuousandunidirectionalmanneratinstantaneous ganelles inlivingaxonsindicatethatmanyorganellesmove folds ofcytosoliclinkerproteins(Karcheretal.,2002). or byindirectinteractionwiththeorganellesurfaceviascaf- tion withtransmembraneproteinsontheorganellesurface, Yang, 2000).Eachmotorbindsitscargobydirectinterac- sin motors)propelorganellesretrogradely(Goldsteinand whereas (andpossiblyalsominusend–directedkine- motors propelorganellesalongmicrotubulesanterogradely, ments alongtheaxisofaxon.Plusend–directedkinesin bules appeartobetheprincipaltracksforlong-rangemove- motor (,,andmyosins).Microtu- crotubule andmicrofilamenttrackspoweredbymolecular established. Membranousorganellesmovealongbothmi- principles underlyingthistransportprocessarenowclearly mechanisms oforganellemovementinaxons,thegeneral nar-Queralt andGoldstein,2001). product ofadistinctpackagingandsortingpathway(Alme- <70mm/d move inslowcomponentasomeneurons,andtubulinmayalsob(Oblingeretal.,1987),butthesignif particles arenotincludedinthistablebecausethereisinsufficientinformationabouttheiroverallrateofmovementat comparison oftheoverallandinstantaneousrates.Otheraxonallytransportedcargos,suchasendoplasmicreticulum,mRNAs, structures (betweenpauses)determinedbylightmicroscopy.Thedutyratioistheproportionoftimethatsp variation betweendifferentcelltypesandstagesofdevelopmentmaturation.Theinstantaneousrateistheactual rates, whereastheratesofslowaxonaltransportaregenerallyquotedasaveragerates).Notethattheseapproximate movements andpauses)determinedbyradioisotopicpulselabeling(fortechnicalreasons,theratesoffastaxonaltransportare Overallrate Each ratecomponentofaxonaltransportcorrespondstoadistinctgroupcargostructures.Theoverallistheaverageor Microfilaments, cytosolicproteincomplexes Mitochondria Endocytic vesicles,lysosomes,autophagosomes Golgi-derived vesicles Cargo structures Table I. f e d c b a Roy etal.,2000; Wangetal.,2000; WangandBrown,2001,2002. Lasek etal.,1984. Lorenz andWillard,1978; GrafsteinandForman,1980. Grafstein andForman,1980. Morris andHollenbeck,1993; LigonandSteward,2000. Breuer etal.,1987; ViancourandKreiter,1993; Nakataetal.,1998; Kaetheretal.,2000. (slow componenta) (slow componentb) (fast retrograde) (fast anterograde) One exceptiontothehighduty ratioofmembranousor- Direct observationsonthemovementofmembranousor- Though muchremainstobelearnedaboutthemolecular

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Volume 160,Number6,2003 0.2–1 mm/d 2–8 mm/d 100–250 mm/d 200–400 mm/d (pulse labeling) e c (.200 ms nnw nnw Unknown Unknown Unknown (0.02–0.09µm/s) (08µ/)0.3–0.7µm/s (<0.8µm/s) e (0.002–0.01 µm/s) 0.3–1 µm/s 0.3–1 (0.002–0.01µm/s) a a 13µ/)1–3µm/s 1–5µm/s (1–3 µm/s) (2–5 µm/s) chondrial movementisgenerallyquotedtobe of axonaltransport(TableI).Themaximalratemito- endocytic vesicles,formingakineticallydistinctcomponent controversy has centeredontheforminwhich thesepro- focused onthe cytoskeletal subunitproteins, andmostofthe rectly inlivingcells(Brown,2000). Mostattentionhasbeen of numerousattemptstoobserve slowaxonaltransportdi- troversy formorethantwodecades, duelargelytothefailure teins movehasbeenthesubject ofintenseinterestandcon- component b(TableI).Themechanism bywhichthesepro- and Lindsey,1983). also betransportedalongaxonsinthismanner(Ellisman sively studied,itappearsthatendoplasmicreticulummay rates ofmovement(Blakeretal.,1981).Thoughnotexten- hibit frequentpausesandreversals,resultinginmuchslower tances, resultinginthemaximalrateofmovement,mostex- chondria maymoverapidlyandcontinuouslyforlongdis- Ligon andSteward,2000).Althoughsomeaxonalmito- broad rangeofoverallrates(MorrisandHollenbeck,1993; grade andretrogrademovementspausesgivingrisetoa rectional manner,withdifferencesinthebalanceofantero- to bethatmitochondriamoveinanintermittentandbidi- 1980). Theexplanationforthistransportbehaviorappears slower (LorenzandWillard,1978;GrafsteinForman, living cells,buttheaveragerateappearstobeconsiderably which iscomparabletotheinstantaneousratesobservedin generally moveatslightlyfaster ratesof a, whereasactinandseveralhundredothercytosolicproteins generally moveatratesof proteins, ,andanumberofothercytosolicproteins groups (Laseketal.,1984).Neuronalintermediatefilament solic proteinscanberesolvedintotwokineticallydistinct In radioisotopicpulselabelingstudies,cytoskeletalandcyto- Movement ofcytoskeletalpolymers (light microscopy) Instantaneous rate b b f d 0.2–1 mm/dinslowcomponent iietoa Low Bidirectional Intermediate High Bidirectional High Retrograde Anterograde ietoaiyDutyratio Directionality time.Notethatactinmayalso rateofmovementthecargo andthatthereisconsiderable generallyquotedasmaximal maximumrate(including icance ofthisisnotclear. end moving,inferredby 2-8 mm/dinslow ribonucleoprotein 20–70 mm/d, The Journal of Cell Biology Remarkably, the keytoobservingthismovement wassimply et al.,2000;Wang etal.,2000;Wangand Brown,2001). the movementsarebothinfrequent andbidirectional(Roy ganelles, buttheaveragerate ofmovementisslowbecause approaching therateofmovement ofmembranousor- Both neurofilamentsandmicrotubules moveatfastrates, in axons,buttheirmovements arenotslowafterall(Fig.1). versy isdisarminglysimple.Cytoskeletal polymersdomove dicate thatthesolutiontoslowaxonaltransportcontro- bules hasbeenobservedinaxons,andtheseobservationsin- al., 1997). the formoffreesubunitsorsmalloligomers(Hirokawa et mers arestationaryandthatcytoskeletalproteinsmovein 1997), whereasothershavearguedthatcytoskeletalpoly- move intheformofassembledpolymers(BaasandBrown, teins move.Somehavearguedthatcytoskeletalproteins permission fromAmericanSocietyforCellBiology. 12:3257–3267, Wang,L.,andA.Brown,Copyright2001,with Images inBarereprintedfrom Images inAwereprovidedbySunitaR.ChadaandPeterJ.Hollenbeck. ment ofmembranousandnonmembranouscargoes.Bar,5 underscores thesimilarityinunderlyingmechanismofmove- move inarapid,intermittent,andbidirectionalmanner,which Brown (2001)fordetails.Bothneurofilamentsandmicrotubules The timeintervalbetweenthesetwoimagesis8s.SeeWangand small arrowheadsmarktheleadingandtrailingendsoffilament. arrowheads marktheedgesofphotobleachedregion,and filament inaphotobleachedaxonofculturedneuron.Thelarge images is3s.(B)AnterogrademovementofaGFP-taggedneuro- field ofviewremainpaused.Thetimeintervalbetweenthesetwo the positionofmovingorganelle.Theothermitochondriain 123 intheaxonofaculturedneuron.Thesmallarrowheadsmark RetrogrademovementofamitochondrionstainedwithRhodamine- (A) Figure 1. Recently themovementofneurofilamentsandmicrotu- Movement ofmitochondriaandneurofilamentsinaxons. Molecular BiologyoftheCell

m. ,

and radialdimensionsoftheaxon. cate andorganizethesepolymersinboththelongitudinal proteins andthatthesemotorsactcooperativelytotranslo- rofilaments eachinteractwithanumberofdifferentmotor seems likelythatmicrotubules,microfilaments,andneu- about themovementofcytoskeletalpolymersinaxons,it (Rao etal.,2002).Althoughmuchremainstobelearned interaction inneurofilamentmovementispresentlyunclear rofilaments alsointeractwithmyosinVa,buttheroleofthis gan, 2001;Helfandetal.,2002).Interestingly,axonalneu- in nonneuronalcells(Prahladetal.,1998;SheaandFlana- anism thatisthoughttomovevimentinalongmicrotubules ments bidirectionallyalongmicrotubulesbythesamemech- and thatdyneinkinesinmaytransportaxonalneurofila- crofilament matrix(SusalkaandPfister,2000;Baas,2002), onal microtubulesanterogradely,perhapsrelativetothemi- eral linesofevidencesuggestthatdyneinmaytransportax- and thetracksalongwhichtheymovearenotknown.Sev- membranous organelles,buttheidentityofthesemotors motors, perhapssimilaroridenticaltomotorsthatmove tubules inaxonsindicatesthattheyaretransportedbyfast mers hasnotyetbeenobserved. ilar behavior,butthemovementofthesecytoskeletalpoly- 2000). Itseemslikelythatmicrofilamentsmayexhibitasim- time pausingduringtheirjourneyalongtheaxon(Brown, pulse labelingstudies)mayspendasmuch99%oftheir ments inmatureaxons(suchasthoseusedforradioisotopic moving. Forexample,ithasbeenestimatedthatneurofila- move withalowdutyratio,spendingmostoftheirtimenot filaments andmicrotubulessuggeststhatthesestructures mitochondria, theslowoverallrateofmovementneuro- inaxonsdescribedabove.As isthecasefor mitochondria haps notfundamentallydissimilarfromthebehaviorof of anterogradeandretrogrademovementspauses,per- ment andmicrotubulemovementisatemporalsummation 2001). Thus,theoverallspeedanddirectionofneurofila- rapid andasynchronousmovement(WangBrown, pears thattheywereprobablynotcapableofdetectingthe tation ofaslowandsynchronousmovement,itnowap- not detectmovementweredesignedwiththeexplicitexpec- a matterofexperimentaldesign;previousstudiesthatdid tures analogous tothemembranousorganelles offastaxonal ciate withacommon classofnonmembranous carrierstruc- months astheytraveldownthe axon,suggestthattheyasso- teins andthefactthattheymove togetherfordays,weeks,or et al.,2002).Thesheernumber anddiversityofthesepro- 1984; PaggiandPetrucci,1992; Dillmanetal.,1996;Rao motor proteinssuchasdynein andmyosin(Laseketal., cytoskeletal proteinssuchasspectrin, tau,anddynactin; bolic enzymessuchascreatinekinase,aldolase,andenolase; and synapsin;regulatoryproteinssuchascalmodulin;meta- clude proteinsinvolvedinvesicledynamicssuchasclathrin solic proteinsthatcompriseaxoplasm.Someexamplesin- in thisrategroup,representingtheentirespectrumofcyto- to rememberthatseveralhundredotherproteinsalsomove on slowaxonaltransportinrecentyears,butitisimportant Cytoskeletal proteinshavebeentheexclusivefocusofstudies Cytoskeletal polymersascarrierstructures The rapidrateofmovementneurofilamentsandmicro- Axonal transport:aunifiedperspective| Brown 819 The Journal of Cell Biology 820 the sameunderlying mechanismbuttheymove atdifferent nonmembranous cargoesarealltransported alongaxonsby of thetimethattheyspendmoving. move atcomparableratesbut theydifferintheproportion diverse asvesicles,mitochondria, andneurofilamentsall axonal transportmaybegenerated byfastmotors;cargoesas as membranousorganellesindicates thatbothfastandslow mers conveyedbyslowaxonaltransportactuallymoveasfast in livingcells.Therecentdiscoverythatcytoskeletalpoly- been ourinabilitytoobserveslowaxonaltransportdirectly cipal reasonforthisprotractedperiodofuncertaintyhas movement hasbeenobscureformostofthattime.Theprin- mechanistic significanceunderlyingthesedifferentratesof transport hasbeenknownformorethan25years,butthe The existenceofdistinctfastandslowcomponentsaxonal Beyond fastandslow:aunifiedperspective but inalleukaryoticcells. the cytosoliccompartmentofcytoplasm,notjustinaxons, insights intothesupramolecularinteractionsthatorganize ous proteincomplexesislikelytoprovidefundamental teins. Theidentificationandcharacterizationofthesevari- tein complexesmaymovebybindingdirectlytomotorpro- moving filaments.Itisalsopossiblethatsomecytosolicpro- form functionalcomplexesthatinturnassociatewiththe microfilaments. Moreprobably,manyoftheseproteins proteins thatmoveinslowcomponentballbinddirectlyto However, itisunlikelythattheseveralhundreddifferent skeleton-associated proteins(e.g.,KnullandWalsh,1992). cluding manythatarenottraditionallythoughtofascyto- teract withawiderangeofdifferentcytosolicproteins,in- support ofthishypothesis,microfilamentsareknowntoin- ments couldbecarrierstructuresforslowcomponentb.In mers. Bythesamelogic,itisalsopossiblethatmicrofila- fied, willalsobefoundtobindthesecytoskeletalpoly- move inthisratecomponent,whichhaveyettobeidenti- A predictionofthishypothesisisthatotherproteins carrier structuresforslowcomponentaofaxonaltransport. it ispossiblethatneurofilamentsandmicrotubulescouldbe is awellcharacterizedmicrotubule-associatedprotein.Thus, interact withneurofilaments(Macioceetal.,1999),andtau proteinsandtubulin.Spectrinisknownto and spectrinbothmoveinslowcomponentaalongwith rectly, tocytoskeletalpolymers.Forexample,tauprotein veyed byslowaxonaltransportcanbind,directlyorindi- ons andthatmanyofthecytosolicproteinsarecon- but itisnowclearthatcytoskeletalpolymersdomoveinax- for slowaxonaltransportwasinitiallymetwithskepticism, mers themselves. well asbytherateandfrequencyofmovementpoly- they spendinassociationwiththecytoskeletalpolymers,as proteins isdeterminedbytheproportionoftimethat According tothishypothesis,thetransportrateofcytosolic on themovingpolymers(Laseketal.,1984,Lasek,1986). other cytosolicproteinsaretransportedbyridingpiggyback ago, isthatcytoskeletalpolymersfulfillthisroleand known. Onehypothesis,firstproposedmorethan15years transport, buttheidentityofthesecarrierstructuresisnot According tothisunifiedperspective, membranousand The ideathatcytoskeletalpolymersarecarrierstructures The JournalofCellBiology

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mental tothebiologyofaxonsasmetabolismitself. membranous componentsisanongoingprocessasfunda- regulation ofthemovementitsmembranousandnon- ues throughoutthelifeofneuron,itislikelythatactive axon growthandmaturation.Sinceaxonaltransportcontin- long-range remodelingoftheneuronalcytoskeletonduring port ofthesestructuresisprobablyessentialforlocaland along theaxon,andthusregulationofaxonaltrans- the principaldeterminantoftheirsteady-statedistribution grade andretrogrademovementspausesislikelytobe neurofilaments andmicrotubules,thebalanceofantero- (Morris andHollenbeck,1993).Likewise,inthecaseof to recruittheseorganellessitesofmetabolicdemand ments andpausesisregulatedduringaxongrowthinorder tochondria, thebalanceofanterogradeandretrogrademove- onal structureandfunction.Forexample,inthecaseofmi- this behaviorislikelytobecriticalformanyaspectsofax- which theyaredistributedalongtheaxon,regulationof ciency withwhichtheyaretransportedandthemannerin havior ofaxonallytransportedcargoesdeterminestheeffi- determines itsdirectionandduration?Sincethemotilebe- quently itdoesso?Andwhenmovementoccur,what or membranousorganellemovespauses,howfre- what determineswhetheraparticularcytoskeletalpolymer and nonmembranouscargoesisregulated.Forexample, the mechanismbywhichmovementofmembranous ing thedifferencebetweenfastandslowaxonaltransportis unique motilebehavior. than theultimatedestination,andthismayexplaintheir sit. Forthesecargoes,thejourneyisperhapsmoreimportant iological, andmetabolicrolesintheaxonduringtheirtran- sembled functionalunitsthatfulfilltheirarchitectural,phys- these organellesandmacromolecularassembliesarepreas- they arenotsimplytheluggageofintracellulartransport; the axon.Althoughwerefertothesestructuresascargoes, of time,andsometimesreversingduringtheirjourneyalong rectional manner,pausingmoreoftenandforlongerperiods endoplasmic reticulum,moveinanintermittentandbidi- trast, cytoskeletalpolymers,mitochondria,andpossiblyalso that theyaredeliveredrapidlytotheirdestination.Incon- ods oftime.Thehighdutyratiotheseorganellesensures idly inaunidirectionalmanner,pausingforonlybriefperi- nents tositesalongtheaxonandattip,moverap- function primarilytodelivermembraneandproteincompo- ganelles onthesecretoryandendocyticpathways,which rates duetodifferencesintheirdutyratio.Membranousor- Accepted: 29January2003 Revised: 28January2003 Submitted: 2December2002 Almenar-Queralt, A., andL.S.Goldstein.2001.Linkers,packages andpathways: tute ofNeurologicalDisordersandStroke. ments onthismanuscript. chondrial movementusedinFig.1A,andtoKittyJensenforhelpfulcom- Thanks toSunitaR.ChadaandPeterJ.Hollenbeckfortheimagesofmito- References Based ontheseconsiderations,acentralquestionunderly- The workintheauthor’slaboratoryissupportedbyNationalInsti- new conceptsinaxonal transport. 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