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Snapshot: Axonal Transport Alison Twelvetrees,1,2 Adam G 950 Cell SnapShot: Axonal Transport 149 Alison Twelvetrees,1,2 Adam G. Hendricks,1 and Erika L.F. Holzbaur1 , May11, 2012©2012Elsevier Inc. DOI 10.1016/j.cell.2012.05.001 1University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA 2Cancer Research UK London Research Institute, London WC2A 3LY, UK Mixed polarity MITOCHONDRIA SYNAPTIC VESICLE PRECURSORS NEUROFILAMENTS microtubules DENSE CORE GRANULES Syntabulin Miro FEZ1 Rab3 Liprin-α Dynein TRAKs JIP1 KBP DENN/MADD KIF5 KIF5A KIF1Bα KIF1A/KIF1Bβ MICROTUBULE AXONS DRAWN TO 5X SCALE: FAST AXONAL TRANSPORT TIME SLOW AXONAL TRANSPORT TIME Axon initial segment e.g., vesicular transport e.g., neurolament transport Selective lter Inhibitory interneuron - 1 mm 4 minutes 3 hours Purkinje cell - 36 mm 2 hours 4.5 days Retinal Ganglion cell - 5 cm 3 hours 6 days Motor neuron - 1 m 2.5 days 125 days Axonal cross-section + Uniform polarity microtubules + + KEY AXONAL MOTOR MOTOR NONMOTOR AXONAL ADAPTORS EARLY ENDOSOMES SIGNALING ENDOSOMES MOTORS PROPERTIES SUBUNITS SUBUNITS (contain p75NTR and Trk receptors) EEA1 TRAKs (Milton) and Miro V 0.8 µm/s KIF5A KLCs Fez1 DISC1 Inactive max JIPs Slp1/CRMP-2 Rab5 KIF5B (not always kinesin-2 Rab7 Rab5 Fs 5-7 pN Huntingtin LIS1/NUDEL See online version for legend and references. Lr 1-2 µm KIF5C required) Syntabulin mNUDC Kinesin-1 APP HSc70 V 0.43 µm/s Axon max KIF3A/B KAP3 Fodrin Fs 5 pN KIF3C terminal Lr 0.45 µm Kinesin-2 LATE ENDOSOMES AND LYSOSOMES AUTOPHAGOSOMES KIF1A DENN/MADD V 1 µm/s max KIF1Bα Liprin-α LAMP1 LC3-II Fs - KIF1Bβ KBP Rab7 Lr 1 µm Inactive Kinesin-3 KIF13B PIP3BP Inactive kinesin-2 Inactive kinesin-1 kinesin-1 Dynactin complex V 0.8 µm/s DICs max LIS1, NudE, NuDEL Fs 1 pN, 6 pN DHC DLICs HAP1/Huntingtin Lr 1 µm DLCs Bicaudal-D family proteins Cytoplasmic dynein Vmax= Maximal velocity Fs = Stall force Lr = Length of run SnapShot: Axonal Transport Alison Twelvetrees,1,2 Adam G. Hendricks,1 and Erika L.F. Holzbaur1 1University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA 2Cancer Research UK London Research Institute, London WC2A 3LY, UK Neuronal axons extend from the cell body over distances ranging from ~100 µm to >1 m. Accordingly, neurons rely on robust intracellular transport of organelles, proteins, mRNA, and signaling molecules. Newly synthesized lipids and proteins are directed to distinct sites along the length of the axon and to the terminus, whereas degradative organelles and signaling complexes move toward the soma. In neurons, kinesin and dynein drive long-range transport along the microtubule cytoskeleton. Axonal microtubules are uniformly polarized such that microtubule plus ends extend distally, in contrast to the mixed polarity microtubule network in dendrites. Members of the kinesin superfamily of motor pro- teins transport cargos toward microtubule plus ends, whereas cytoplasmic dynein drives transport toward microtubule minus ends. Consistent with an essential role for axonal transport in the neuron, defects in kinesin, dynein, or the microtubule cytoskeleton cause neurodegenerative disease in humans and mouse models. Further, defects in axonal transport have been found in models of many degenerative diseases, including amyotrophic lateral sclerosis and Alzheimer’s and Huntington’s diseases, indicating that inhibition of this pathway may be a common aspect of neurodegeneration. Thus, a thorough mechanistic analysis of axonal transport is required to better understand neurodegenerative disease. In addition, the polarized microtubule cytoskeleton and long length scales make transport along the axon a useful model system for studying fundamental aspects of microtubule-based transport. Cytoskeleton Cargos that are newly synthesized in the soma are targeted distinctly to either the axonal or somato-dendritic compartments. The axon initial segment has been shown to act as a selective filter for axonal transport, which may contribute to preferential trafficking of axonally restricted cargos. However, the polarity of the microtubule cytoskeleton is also likely to be a major factor in this sorting. The unipolar nature of microtubules in axons prevents dynein from driving transport into this cellular compartment but permits dynein- driven transport into dendrites. In addition, microtubule organization and posttranslational modifications of tubulin also contribute to sorting mechanisms, as different motor proteins demonstrate inherent preferences for microtubule subpopulations. Motor Proteins Many intracellular cargos are transported bidirectionally by small teams (1–10) of kinesin and dynein motors. Although many cargos have opposite polarity motors bound, the motility of these organelles can vary greatly. For example, late endosomes and lysosomes exhibit bidirectional motility, characterized by frequent directional switching and paus- ing. In contrast, autophagosomes also have both kinesin and dynein bound yet move predominantly in the retrograde direction with few directional switches, suggesting that the activity of bound kinesin motors is tightly regulated. Other cargos, such as mitochondria and neurofilaments, exhibit long pauses interspersed with short bursts of motility. The diverse motility characteristics of various cargos can be partially explained by the biophysical properties of the motor proteins that drive their transport. For example, kinesin-1 and kinesin-2 produce similar forces, but kinesin-2 is less processive, particularly under load. Accordingly, late endosomes that are driven primarily by kinesin-2 and dynein exhibit more bidirectional motility than early endosomes, which are transported primarily by kinesin-1 and dynein. Adaptors and Scaffolding Molecules An additional level of regulation for transport specificity and selectivity occurs through the use of adaptor proteins or scaffolds to couple motor proteins to their cargo, and multiple specific linkage mechanisms have now been identified. Indeed, mitochondria utilize several adaptors to recruit and regulate kinesin. Many of these motor-adaptor com- plexes are regulated by the GTPase action of Rab proteins, as well as phosphorylation and calcium binding. Not only do these interactions have the ability to target motors to specific organelles, they may also serve to regulate the activity of the motors in response to signaling cascades such as response to axonal injury. Key Questions in Axonal Transport Though much progress has been made in characterizing the motility of cargos in the axon and the motor proteins driving transport, many questions remain. (1) Bidirectional transport is driven by teams of opposite polarity motors. How do motor proteins function collectively? What regulatory mechanisms exist to bias bidirectional transport between primarily anterograde, retrograde, or bidirectional motility? (2) For mitochondria, a specialized set of adaptors modulate kinesin activity. Do similar adaptors exist for other car- gos? (3) Neurons receive an extensive array of intercellular signals that regulate their activity. What is the role of signaling cascades in specifically regulating trafficking events? (4) Dynein’s binding partners dynactin, NudE(L), and LIS1 have been shown to modify processivity and force production. How do motor binding partners regulate motor function during axonal transport? (5) How do microtubule-associated proteins (MAPs) and cytoskeletal posttranslational modifications modulate motility? For instance, the MAP tau has been shown to inhibit kinesin-1 more strongly than dynein. (6) Although many protein complexes have been identified that link kinesin motors to membranous organelles (e.g., Miro and the TRAKs) or enhance their processivity (e.g., liprin-α), very few dynein-specific binding scaffolds have been found to date. Does dynein require similar targeting mechanisms to those seen for kinesin motors? REFERENCES Dixit, R., Ross, J.L., Goldman, Y.E., and Holzbaur, E.L. (2008). Differential regulation of dynein and kinesin motor proteins by tau. Science 319, 1086–1089. Hendricks, A.G., Perlson, E., Ross, J.L., Schroeder, H.W., III, Tokito, M., and Holzbaur, E.L. (2010). Motor coordination via a tug-of-war mechanism drives bidirectional vesicle trans- port. Curr. Biol. 20, 697–702. Hirokawa, N., Niwa, S., and Tanaka, Y. (2010). Molecular motors in neurons: transport mechanisms and roles in brain function, development, and disease. Neuron 68, 610–638. Kapitein, L.C., Schlager, M.A., Kuijpers, M., Wulf, P.S., van Spronsen, M., MacKintosh, F.C., and Hoogenraad, C.C. (2010). Mixed microtubules steer dynein-driven cargo transport into dendrites. Curr. Biol. 20, 290–299. Maday, S., Wallace, K.E., and Holzbaur, E.L. (2012). Autophagosomes initiate distally and mature during transport toward the cell soma in primary neurons. J. Cell Biol. 196, 407– 417. McKenney, R.J., Vershinin, M., Kunwar, A., Vallee, R.B., and Gross, S.P. (2010). LIS1 and NudE induce a persistent dynein force-producing state. Cell 141, 304–314. Pilling, A.D., Horiuchi, D., Lively, C.M., and Saxton, W.M. (2006). Kinesin-1 and Dynein are the primary motors for fast transport of mitochondria in Drosophila motor axons. Mol. Biol. Cell 17, 2057–2068. Salinas, S., Bilsland, L.G., and Schiavo, G. (2008). Molecular landmarks along the axonal route: axonal transport in health and disease. Curr. Opin. Cell Biol. 20, 445–453. Sheng, Z.H., and Cai, Q. (2012). Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration. Nat. Rev. Neurosci. 13, 77–93. Song, A.H., Wang, D., Chen, G., Li, Y., Luo, J., Duan, S., and Poo, M.M. (2009). A selective filter for cytoplasmic transport at the axon initial segment. Cell 136, 1148–1160. Soppina, V., Rai, A.K., Ramaiya, A.J., Barak, P., and Mallik, R. (2009). Tug-of-war between dissimilar teams of microtubule motors regulates transport and fission of endosomes. Proc. Natl. Acad. Sci. USA 106, 19381–19386. Wang, L., Ho, C.L., Sun, D., Liem, R.K., and Brown, A. (2000). Rapid movement of axonal neurofilaments interrupted by prolonged pauses. Nat. Cell Biol. 2, 137–141. 950.e1 Cell 149, May 11, 2012 ©2012 Elsevier Inc. DOI 10.1016/j.cell.2012.05.001.
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