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Rosenand G. Berke,J. CettBiol.95137-143,1982.The RockefellerUniversityPress.)A similar cooperative feedback loop seems to operate in many otherinstances of cell polarization. A particularly interesting example is the killing ofspecific target cells byT lymphocytes. These cells are a critical component of thevertebrate's adaptive immune response to infection by viruses.
T cells, like neu-trophils, use actin-based motility to crawl through the body's tissue and findinfected target cells. \Mhen a T cell comes into contact with a virus-infected celland its receptors recognize foreign viral antigens on the surface of the target cell,the same polarization machinery is engaged in a very different way to facilitatekilting of the target cell. Rac is activated at the point of cell-cell contact andcausesactin polymerization at this site, creating a specialized region of the cortex. This specialized site causes the centrosome to reorient, moving with itsmicrotubules to the zone of T-cell-target contact (Figure f6-f03). The microtubules, in turn, position the Golgi apparatus right under the contact zone'focusing the killing machinery onto the target cell.
The mechanism of killing isdiscussedin Chapter 25 (seeFigure 25-47).of NeuronsDependsSpecializationTheComplexMorphologicalon the CytoskeletonFor our final case study of the ways that the intrinsic properties of the eucaryoticcytoskeleton enable specific and enormously complicated large-scale cell behaviors, we examine the neuron.
Neurons begin life in the embryo as unremarkablecells, which use actin-based motility to migrate to specific locations. Once there,however, they send out a series of long specialized processes that will eitherreceive electrical signals (dendrites) or transmit electrical signals (axons) to theirThe beautiful and elaborate branching morphology of axonstarget cells.lesneurons to form tremendously complex signaling netand dendriworks, interacting with many other cells simultaneously and making possible thecomplicated and often unpredictable behavior of the higher animals.
Both axonsand dendrites (collectively called.neurites) are filled with bundles of microtubulesthat are critical to both their structure and their function.In axons, all the microtubules are oriented in the same direction, with theirminus end pointing back toward the cell body and their plus end pointing forward toward the axon terminals (Figure f 6-104). The microtubules do not reach(8)10pm1048Chapter16:TheCytoskeletono v e s i c l ew i t h b o u n d d y n e i no v e s i c l ew i t h b o u n d k i n e s i nmicrotubuler(A)FIBRoBLAST(B)NEURoNfrom the cell body all the way to the axon terminals; each is typically only a fewmicrometers in length, but large numbers are staggered in an overlapping array.This set of aligned microtubule tracks acts as a highway to transport many specific proteins, protein-containing vesicles, and mRNAs to the axon terminals,where synapsesmust be constructed and maintained.
The longest axon in thehuman body reachesfrom the base of the spinal cord to the foot, being up to ameter in length.Mitochondria, large numbers of specific proteins in transport vesicles,andsynaptic vesicle precursors make the long journey in the forward (anterograde)direction. They are carried there by plus-end-directed kinesin-family moror proteins that can move them a meter in as little as two or three days, which is a greatimprovement over diffrrsion, which would take approximately several decadesto move a mitochondrion this distance.
Many members of the kinesin superfamily contribute to this anterograde axonal transport, most carrying sp"iificsubsets of membrane-enclosed organelles along the microtubuler. ih" g."utdiversity of the kinesin family motor proteins used in axonal transport suggeststhat they are involved in targeting their cargo to specific structures near the terminus or along the way, as well as in cargo movement.
old components from theaxon terminals are carried back to the cell body for degradation and recycling bya retrograde axonal transport. This transport occurs along the same set of oriented microtubules, but it relies on cytoplasmic dynein, t-tri.tr is a minus-enddirected motor protein. Retrogradetransport is also critical for communicatingthe presence of growth and survival signals received by the nerve terminus backto the nucleus, in order to influence gene expression.one form of human peripheral neuropathy, charcot-Marie-Tooth disease,iscaused by a point mutation in a particular kinesin family member that transports slmaptic vesicle precursors dovrrnthe axon.
other kinds of neurodegenerative diseases such as Alzheimer's disease may also be caused in part by dlsruptions in neuronal trafficking; as pointed out previously, the amyloid pr".r.r^o,protein APP is part of a protein complex that serves as a receptor for kinesin-lbinding to other axonal transport vesicles.Axonal structure depends on the axonal microtubules, as well as on the contributions of the other two major cytoskeletal systems-actin filaments andintermediate filaments.
Actin filaments line the cortex of the axon, just beneaththe plasma membrane, and actin-based motor proteins such as myosin v arealso abundant in the rxon, presumably to help move materials. Neurofilaments,the specialized intermediate filaments of nerve cells, provide the most important structural support in the axon. A disruption in neurofilament structure, orin the cross-linking proteins that attach the neurofilaments to the microtubulesand actin filaments distributed along the ixon, can result in axonal disorganization and eventually axonal degeneration.The construction ofthe elaborate branching architecture ofthe neuron during embryonic development requires actin-based motility.
As mentioned earlier,the-tips of growing axons and dendrites extend by means of a growth cone, a specialized motile structure rich in actin (Figure 16-105). Mosi neuronal growthcones produce filopodia, and some make lamellipodia as well. The protrusionFigurel6-104 Microtubuleorganizationin fibroblastsand neurons.(A)In afibroblast,microtubulesemanateoutwardfrom the centrosomein themiddleof the cell.Vesicleswith Dlus-enddirectedkinesinattachedmove outward,and vesicleswith minus-end-directeddyneinattachedmove inward.(B)In aneuron,microtubuleorganizationis morecomplex.In the axon,all microtubulessharethe samepolarity,with the plusends pointing outward toward the axonterminus.No one microtubulestretchesthe entirelengthofthe axon;instead,short overlappingsegmentsof parallelmicrotubulesmakethe tracksfor fastaxonaltransport.In dendrites,themicrotubulesare of mixed polarity,withsomeplusendspointingoutwardandsomepointinginward.104!lANDCELLBEHAVIORTHECYTOSKELETONtt(B)1 0p m1 0p mFigure 16-1 05 Neuronalgrowth cones.<AAGA>(A)Scanningelectronmicrographof two growth conesat the end of aneurite,put out by a chicksympatheticsingleneuronin culture.Here,a previouslygrowth cone hasrecentlysplit into two'Notethe manyfilopodiaand the largeof theThetaut appearancelamellipodia.neuriteis due to tensiongeneratedby theforward movementof the growth cones,which are often the only firm points ofattachmentof the axonto the substratum.(B)Scanningelectronmicrographof thegrowth cone of a sensoryneuroncrawlingoverthe innersurfaceof the epidermisof aXenopustadpole.(A,from D.
Bray,in CellA. CurtisandBehaviour[R.Bellairs,UK:CambridgeG.Dunn,eds.l.Cambridge,UniversityPress,1982;B,from A. Roberts,BrainRes.118:526-530,1976.Withpermissionfrom Elsevier.)and stabilization of growth-cone filopodia are exquisitely sensitive to environmental cues.Some cells secretesoluble proteins such as netrin to attract or repelgrowth cones. These modulate the structure and motility of the growth conecytoskeleton by altering the balance between Rac activity and Rho activity at theleading edge (see Figure 15-62).In addition, there are fixed guidance markersalong the way, attached to the extracellular matrix or to the surfaces of cells.\Mhen a filopodium encounters such a "guidepost" in its exploration, it quicklyforms adhesive contacts.
It is thought that a myosin-dependent collapse of theactin meshwork in the unstabilized part of the growth cone then causes thedeveloping ixon to turn toward the guidepost.Thus, a complex combination of positive and negative signals,both solubleand insoluble, accurately guide the growth cone to its final destination. Microtubules then reinforce the directional decisions made by the actin-rich protrusive structures at the leading edge of the growth cone.
Microtubules from theaxonal parallel array just behind the growth cone are constantly growing into thegrowth cone and shrinking back by dynamic instability. Adhesive guidance signals are somehow relayed to the dynamic microtubule ends, so that microtubules growing in the correct direction are stabilized against disassembly. Inthis way, a microtubule-rich axon is left behind, marking the path that thegrowth cone has traveled.Dendrites are generally much shorter projections than axons' and theyreceive synaptic inputs rather than being specialized for sending signals likeaxons. The microtubules in dendrites all lie parallel to one another but theirpolarities are mixed, with some pointing their plus ends toward the dendrite tip,while others point back toward the cell body. Nevertheless,dendrites also formas the result of growth-cone activity.
Therefore, it is the growth cones at the tipsof axons and dendrites that create the intricate, highly individual morphology ofeach mature neuronal cell (Figure f 6-f 06).a x o n ( l e s st h a n 1 m m t om o r et h a n 1 m i n l e n g t h )dendritesreceives y n a p t i ci n p u t sc e l lb o d yzlrmt e r m i n a lb r a n c h e so fa x o n m a k es y n a p s eosntarget cellsFigure16-106 The complexarchitectureof a vertebrate neuron.The neuronshown is from the retinaof a monkey.The arrowsindicatethe directionof travelsignalalongthe axon.of the electricalThe longestand largestneuronsin thehuman body extendfor a distanceofabout 1 m (1 millionUm),from the baseof the spinalcord to the tip of the bigtoe,and havean axondiameterof 15 pm.on(Adaptedfrom B.B.Boycott,in Essaysandthe NervousSystem[R.BellairsE.G.Gray,eds.l.Oxford,UK:ClarendonPress,1974.)1050Chapter16:TheCytoskeleton(B)2040timein mins60 |lolr#80Although the neurons of the central nervous system are long-lived cells,theyare by no means static.
synapses are constantly being created, strengthened,weakened, and eliminated as the brain learns, evaluates,and forgets. uigh-r"rolution imaging of the structure of neurons in the brains of adult mice hasrevealed that neuronal morphology is undergoing constant rearrangement assynapsesare forged and broken (Figure l6-10z). These actin-dependent rearrangements are rhought to be critical in learning and long-term memory. In thisway, the cltoskeleton provides the engine for construction of the entire nervoussystem, as well as producing the supporting structures that strengthen, stabilize,and maintain its parts.Figure16-107Rapidchangesin dendritestructurewithin a living mousebrain.(A)lmageof corticalneuronsin a transgenicmousethat hasbeenengineeredto expressgreenfluorescentprotein in a smallfractionof its braincells.Changesin thesebrainneuronsand their projectionscan befollowedfor monthsusinghighlysensitivefluorescencemicroscopy.To makethispossible,the mouseis subjectedto anoperationthat introducesa smalltransparentwindowthroughits skull,and itis anesthetizedeachtime that an imageis(B)A singledendrite,imagedoverrecorded.the period of 80 minutes,demonstratesthatdendritesareconstantlysendingout andretractingtiny actin-dependentprotrusionsto createthe dendriticspinesthat receivethe vast majorityof excitatorysynapsesfrom axonsin the brain.Thosespinesthatbecomestabilizedand persistfor monthsarethoughtto be importantfor brainfunction,and may be involvedin long-termmemory.(Courtesyof KarelSvoboda.)SummaryTwo distinct typesof specializedstructures in eucaryotic cells areformed from hightyordered arrays of motor proteins that moue on stabilized filament tracks.
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