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The cellular mechanisms that maintain neuronal polarity

Nature Reviews Neuroscience volume 17, pages 611–622 (2016)Cite this article

Subjects

Key Points

  • Nearly every aspect of neuronal function depends on the accurate localization of polarized membrane proteins to the axon or dendrites.

  • Selective sorting, selective transport and selective delivery are the key events for maintaining neuronal polarity.

  • Some of the sorting signals and sorting adaptors that mediate the targeting of dendritic proteins have been identified. By contrast, little is known about the mechanisms underlying axonal protein sorting.

  • Selective microtubule-based transport is crucial for the targeting of both axonal and dendritic proteins. The basis for selective transport depends on the regulation of motor proteins, but the underlying mechanisms remain controversial.

  • There must be links between the process of protein sorting, which determines the cargoes present in a vesicle and hence the identity of a vesicle, and the recruitment of the correct motors, SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) and tethers, which determine the fate of a vesicle. Almost nothing is yet known about these links.

Abstract

As polarized cells, neurons maintain different sets of resident plasma membrane proteins in their axons and dendrites, which is consistent with the different roles that these neurites have in electrochemical signalling. Axonal and dendritic proteins are synthesized together within the somatodendritic domain; this raises a fundamental question: what is the nature of the intracellular trafficking machinery that ensures that these proteins reach the correct domain? Recent studies have advanced our understanding of the processes underlying the selective sorting and selective transport of axonal and dendritic proteins and have created potential avenues for future progress.

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Figure 1: Neuronal membrane trafficking.
Figure 2: The trafficking of polarized proteins in neurons.

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References

  1. Craig, A. M. & Banker, G. Neuronal polarity. Annu. Rev. Neurosci. 17, 267–310 (1994).

    CAS  PubMed  Google Scholar 

  2. Peters, A., Palay, S. L. & Webster, H. D. The Fine Structure of the Nervous System: The Neurons and Supporting Cells (Oxford Univ. Press, 1991).

    Google Scholar 

  3. Roy, S. Seeing the unseen: the hidden world of slow axonal transport. Neuroscientist 20, 71–81 (2014).

    PubMed  Google Scholar 

  4. Blackstone, C., O'Kane, C. J. & Reid, E. Hereditary spastic paraplegias: membrane traffic and the motor pathway. Nat. Rev. Neurosci. 12, 31–42 (2011).10.1038/nrn2946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Encalada, S. E. & Goldstein, L. S. B. Biophysical challenges to axonal transport: motor-cargo deficiencies and neurodegeneration. Annu. Rev. Biophys. 43, 141–169 (2014).

    CAS  PubMed  Google Scholar 

  6. Chevalier-Larsen, E. & Holzbaur, E. L. F. Axonal transport and neurodegenerative disease. Biochim. Biophys. Acta 1762, 1094–1108 (2006).

    CAS  PubMed  Google Scholar 

  7. Hunn, B. H. M., Cragg, S. J., Bolam, J. P., Spillantini, M. G. & Wade-Martins, R. Impaired intracellular trafficking defines early Parkinson's disease. Trends Neurosci. 38, 178–188 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Guo, Y., Sirkis, D. W. & Schekman, R. Protein sorting at the trans-Golgi network. Annu. Rev. Cell Dev. Biol. 30, 169–206 (2014).

    CAS  PubMed  Google Scholar 

  9. Chia, P. Z. C. & Gleeson, P. A. Membrane tethering. F1000Prime Rep. 6, 74 (2014).

    PubMed  PubMed Central  Google Scholar 

  10. Sztul, E. & Lupashin, V. Role of vesicle tethering factors in the ER–Golgi membrane traffic. FEBS Lett. 583, 3770–3783 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Jahn, R. & Scheller, R. H. SNAREs — engines for membrane fusion. Nat. Rev. Mol. Cell Biol. 7, 631–643 (2006).

    CAS  PubMed  Google Scholar 

  12. Vale, R. D. The molecular motor toolbox for intracellular transport. Cell 112, 467–480 (2003).

    CAS  PubMed  Google Scholar 

  13. Hirokawa, N., Noda, Y., Tanaka, Y. & Niwa, S. Kinesin superfamily motor proteins and intracellular transport. Nat. Rev. Mol. Cell Biol. 10, 682–696 (2009).

    CAS  PubMed  Google Scholar 

  14. Vallee, R. B., McKenney, R. J. & Ori-McKenney, K. M. Multiple modes of cytoplasmic dynein regulation. Nat. Cell Biol. 14, 224–230 (2012).

    CAS  PubMed  Google Scholar 

  15. Bhabha, G., Johnson, G. T., Schroeder, C. M. & Vale, R. D. How dynein moves along microtubules. Trends Biochem. Sci. 41, 94–105 (2015).

    PubMed  PubMed Central  Google Scholar 

  16. Akhmanova, A. & Hammer, J. A. III. Linking molecular motors to membrane cargo. Curr. Opin. Cell Biol. 22, 479–487 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Hutagalung, A. H. & Novick, P. J. Role of rab GTPases in membrane traffic and cell physiology. Physiol. Rev. 91, 119–149 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Julie, G. Donaldson, C. L. J. Arf family G proteins and their regulators: roles in membrane transport, development and disease. Nat. Rev. Mol. Cell Biol. 12, 362–375 (2011).

    Google Scholar 

  19. Burack, M. A., Silverman, M. A. & Banker, G. The role of selective transport in neuronal protein sorting. Neuron 26, 465–472 (2000).

    CAS  PubMed  Google Scholar 

  20. Al-Bassam, S., Xu, M., Wandless, T. J. & Arnold, D. B. Differential trafficking of transport vesicles contributes to the localization of dendritic proteins. Cell Rep. 2, 89–100 (2012). This paper presents evidence in support of the myosin hypothesis for selective dendritic transport.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Farías, G. G. et al. Signal-mediated, AP-1/clathrin-dependent sorting of transmembrane receptors to the somatodendritic domain of hippocampal neurons. Neuron 75, 810–823 (2012). This study shows that AP1 mediates the sorting of several dendritically polarized proteins.

    PubMed  PubMed Central  Google Scholar 

  22. Jensen, C. S. et al. Specific sorting and post-Golgi trafficking of dendritic potassium channels in living neurons. J. Biol. Chem. 289, 10566–10581 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Nakata, T. & Hirokawa, N. Microtubules provide directional cues for polarized axonal transport through interaction with kinesin motor head. J. Cell Biol. 162, 1045–1055 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Sampo, B., Kaech, S., Kunz, S. & Banker, G. Two distinct mechanisms target membrane proteins to the axonal surface. Neuron 37, 611–624 (2003).

    CAS  PubMed  Google Scholar 

  25. Lee, K. H. et al. KIF21A-mediated axonal transport and selective endocytosis underlie the polarized targeting of NCKX2. J. Neurosci. 32, 4102–4117 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Bel, C., Oguievetskaia, K., Pitaval, C., Goutebroze, L. & Faivre-Sarrailh, C. Axonal targeting of Caspr2 in hippocampal neurons via selective somatodendritic endocytosis. J. Cell Sci. 122, 3403–3413 (2009).

    CAS  PubMed  Google Scholar 

  27. Wisco, D. et al. Uncovering multiple axonal targeting pathways in hippocampal neurons. J. Cell Biol. 162, 1317–1328 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. MacGillavry, H. D., Kerr, J. M. & Blanpied, T. A. Lateral organization of the postsynaptic density. Mol. Cell Neurosci. 48, 321–331 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Dzhashiashvili, Y. et al. Nodes of Ranvier and axon initial segments are ankyrin G-dependent domains that assemble by distinct mechanisms. J. Cell Biol. 177, 857–870 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. West, A. E., Neve, R. L. & Buckley, K. M. Identification of a somatodendritic targeting signal in the cytoplasmic domain of the transferrin receptor. J. Neurosci. 17, 6038–6047 (1997).

    CAS  PubMed  Google Scholar 

  31. Jareb, M. & Banker, G. The polarized sorting of membrane proteins expressed in cultured hippocampal neurons using viral vectors. Neuron 20, 855–867 (1998).

    CAS  PubMed  Google Scholar 

  32. Silverman, M. A. et al. Motifs that mediate dendritic targeting in hippocampal neurons: a comparison with basolateral targeting signals. Mol. Cell Neurosci. 29, 173–180 (2005).

    CAS  PubMed  Google Scholar 

  33. Owen, D. J., Collins, B. M. & Evans, P. R. Adaptors for clathrin coats: structure and function. Annu. Rev. Cell Dev. Biol. 20, 153–191 (2004).

    CAS  PubMed  Google Scholar 

  34. Robinson, M. S. Adaptable adaptors for coated vesicles. Trends Cell Biol. 14, 167–174 (2004).

    CAS  PubMed  Google Scholar 

  35. Bonifacino, J. S. Adaptor proteins involved in polarized sorting. J. Cell Biol. 204, 7–17 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Kirchhausen, T., Owen, D. & Harrison, S. C. Molecular structure, function, and dynamics of clathrin-mediated membrane traffic. Cold Spring Harb. Perspect. Biol. 6, a016725 (2014).

    PubMed  PubMed Central  Google Scholar 

  37. Sang Yoon, P. & Xiaoli, G. Adaptor protein complexes and intracellular transport. Biosci. Rep. 34, e00123 (2014).

    Google Scholar 

  38. Popova, N. V., Deyev, I. E. & Petrenko, A. G. Clathrin-mediated endocytosis and adaptor proteins. Acta Naturae 5, 62–73 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Fields, I. C., King, S. M., Shteyn, E., Kang, R. S. & Folsch, H. Phosphatidylinositol 3,4,5-trisphosphate localization in recycling endosomes is necessary for AP-1B–dependent sorting in polarized epithelial cells. Mol. Biol. Cell 21, 95–105 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Shteyn, E., Pigati, L. & Folsch, H. Arf6 regulates AP-1B–dependent sorting in polarized epithelial cells. J. Cell Biol. 194, 873–887 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Matsuda, S. et al. Accumulation of AMPA receptors in autophagosomes in neuronal axons lacking adaptor protein AP-4. Neuron 57, 730–745 (2008). This report shows that AP4 mediates the sorting of AMPA receptors.

    CAS  PubMed  Google Scholar 

  42. Brown, M. D., Banker, G. A., Hussaini, I. M., Gonias, S. L. & VandenBerg, S. R. Low density lipoprotein receptor-related protein is expressed early and becomes restricted to a somatodendritic domain during neuronal differentiation in culture. Brain Res. 747, 313–317 (1997).

    CAS  PubMed  Google Scholar 

  43. Kang, R. S. & Folsch, H. ARH cooperates with AP-1B in the exocytosis of LDLR in polarized epithelial cells. J. Cell Biol. 193, 51–60 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Donoso, M. et al. Polarized traffic of LRP1 involves AP1B and SNX17 operating on Y-dependent sorting motifs in different pathways. Mol. Biol. Cell 20, 481–497 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Mameza, M. G. et al. Characterization of the adaptor protein ARH expression in the brain and ARH molecular interactions. J. Neurochem. 103, 927–941 (2007).

    CAS  PubMed  Google Scholar 

  46. Rivera, J. F., Ahmad, S., Quick, M. W., Liman, E. R. & Arnold, D. B. An evolutionarily conserved dileucine motif in Shal K+ channels mediates dendritic targeting. Nat. Neurosci. 6, 243–250 (2003).

    CAS  PubMed  Google Scholar 

  47. Diao, F., Chaufty, J., Waro, G. & Tsunoda, S. SIDL interacts with the dendritic targeting motif of Shal (Kv4) K+ channels in Drosophila. Mol. Cell Neurosci. 45, 75–83 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Kozik, P., Francis, R. W., Seaman, M. N. J. & Robinson, M. S. A. Screen for endocytic motifs. Traffic 11, 843–855 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Yap, C. C. et al. Pathway selection to the axon depends on multiple targeting signals in NgCAM. J. Cell Sci. 121, 1514–1525 (2008).

    CAS  PubMed  Google Scholar 

  50. Yap, C. C. C., Lasiecka, Z. M., Caplan, S. & Winckler, B. Alterations of EHD1/EHD4 protein levels interfere with L1/NgCAM endocytosis in neurons and disrupt axonal targeting. J. Neurosci. 30, 6646–6657 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Lasiecka, Z. M., Yap, C. C., Caplan, S. & Winckler, B. Neuronal early endosomes require EHD1 for L1/NgCAM trafficking. J. Neurosci. 30, 16485–16497 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Gu, C. & Barry, J. Function and mechanism of axonal targeting of voltage-sensitive potassium channels. Prog. Neurobiol. 94, 115–132 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Gu, C., Jan, Y. N. & Jan, L. Y. A conserved domain in axonal targeting of Kv1 (Shaker) voltage-gated potassium channels. Science 301, 646–649 (2003).

    CAS  PubMed  Google Scholar 

  54. Rivera, J. F., Chu, P. J. & Arnold, D. B. The T1 domain of Kv1.3 mediates intracellular targeting to axons. Eur. J. Neurosci. 22, 1853–1862 (2005).

    PubMed  Google Scholar 

  55. Gu, C. et al. The microtubule plus-end tracking protein EB1 is required for Kv1 voltage-gated K+ channel axonal targeting. Neuron 52, 803–816 (2006).

    CAS  PubMed  Google Scholar 

  56. Li, P., Merrill, S. A., Jorgensen, E. M. & Shen, K. Two clathrin adaptor protein complexes instruct axon-dendrite polarity. Neuron 90, 564–580 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Burton, P. R. & Paige, J. L. Polarity of axoplasmic microtubules in the olfactory nerve of the frog. Proc. Natl Acad. Sci. USA 78, 3269–3273 (1981).

    CAS  PubMed  Google Scholar 

  58. Heidemann, S. R. et al. Spatial organization of axonal microtubules. J. Cell Biol. 99, 1289–1295 (1984).

    CAS  PubMed  Google Scholar 

  59. Baas, P. W., Deitch, J. S., Black, M. M. & Banker, G. Polarity orientation of microtubules in hippocampal neurons: uniformity in the axon and nonuniformity in the dendrite. Proc. Natl Acad. Sci. USA 85, 8335–8339 (1988).

    CAS  PubMed  Google Scholar 

  60. Stepanova, T. et al. Visualization of microtubule growth in cultured neurons via the use of EB3-GFP (end-binding protein 3-green fluorescent protein). J. Neurosci. 23, 2655–2664 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Baas, P. W. & Lin, S. Hooks and comets: the story of microtubule polarity orientation in the neuron. Dev. Neurobiol. 71, 403–418 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Baas, P. W., Black, M. M. & Banker, G. A. Changes in microtubule polarity orientation during the development of hippocampal neurons in culture. J. Cell Biol. 109, 3085–3094 (1989).

    CAS  PubMed  Google Scholar 

  63. Yau, K. W. et al. Dendrites in vitro and in vivo contain microtubules of opposite polarity and axon formation correlates with uniform plus-end-out microtubule orientation. J. Neurosci. 36, 1071–1085 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Kapitein, L. C. & Hoogenraad, C. C. Building the neuronal microtubule cytoskeleton. Neuron 87, 492–506 (2015).

    CAS  PubMed  Google Scholar 

  65. Leterrier, C. et al. End-binding proteins EB3 and EB1 link microtubules to ankyrin G in the axon initial segment. Proc. Natl Acad. Sci. USA 108, 8826–8831 (2011).

    CAS  PubMed  Google Scholar 

  66. van Beuningen, S. F. B. et al. TRIM46 controls neuronal polarity and axon specification by driving the formation of parallel microtubule arrays. Neuron 88, 1208–1226 (2015).

    CAS  PubMed  Google Scholar 

  67. Silverman, M. A. et al. Expression of kinesin superfamily genes in cultured hippocampal neurons. Cytoskeleton (Hoboken) 67, 784–795 (2010).

    CAS  Google Scholar 

  68. Roberts, A. J., Kon, T., Knight, P. J., Sutoh, K. & Burgess, S. A. Functions and mechanics of dynein motor proteins. Nat. Rev. Mol. Cell Biol. 14, 713–726 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Jacobson, C., Schnapp, B. & Banker, G. A. A change in the selective translocation of the Kinesin-1 motor domain marks the initial specification of the axon. Neuron 49, 797–804 (2006).

    CAS  PubMed  Google Scholar 

  70. Yang, R., Bentley, M., Huang, C. F. & Banker, G. Analyzing kinesin motor domain translocation in cultured hippocampal neurons. Methods Cell Biol. 131, 217–232 (2015).

    PubMed  PubMed Central  Google Scholar 

  71. Vale, R. D. et al. Direct observation of single kinesin molecules moving along microtubules. Nature 380, 451–453 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Friedman, D. S. & Vale, R. D. Single-molecule analysis of kinesin motility reveals regulation by the cargo-binding tail domain. Nat. Cell Biol. 1, 293–297 (1999).

    CAS  PubMed  Google Scholar 

  73. Cai, D., McEwen, D. P., Martens, J. R., Meyhofer, E. & Verhey, K. J. Single molecule imaging reveals differences in microtubule track selection between kinesin motors. PLoS Biol. 7, e1000216 (2009).

    PubMed  PubMed Central  Google Scholar 

  74. Soppina, V. et al. Dimerization of mammalian kinesin-3 motors results in superprocessive motion. Proc. Natl Acad. Sci. USA 111, 5562–5567 (2014).

    CAS  PubMed  Google Scholar 

  75. Huang, C. F. & Banker, G. The translocation selectivity of the kinesins that mediate neuronal organelle transport. Traffic 13, 549–564 (2012). This systematic screen of kinesin motor domains shows that no motors are dendrite selective.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Kapitein, L. C. et al. Probing intracellular motor protein activity using an inducible cargo trafficking assay. Biophys. J. 99, 2143–2152 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Kapitein, L. C. et al. Mixed microtubules steer dynein-driven cargo transport into dendrites. Curr. Biol. 20, 290–299 (2010). This study, which introduced the peroxisome assay for evaluating motor selectivity, shows that cargoes can be targeted selectively into dendrites and provides evidence for the dynein hypothesis for selective dendritic transport.

    CAS  PubMed  Google Scholar 

  78. Ally, S., Larson, A. G., Barlan, K., Rice, S. E. & Gelfand, V. I. Opposite-polarity motors activate one another to trigger cargo transport in live cells. J. Cell Biol. 187, 1071–1082 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Lipka, J., Kapitein, L. C., Jaworski, J. & Hoogenraad, C. C. Microtubule-binding protein doublecortin-like kinase 1 (DCLK1) guides kinesin-3-mediated cargo transport to dendrites. EMBO J. 35, 302–318 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Setou, M., Nakagawa, T., Seog, D. H. & Hirokawa, N. Kinesin superfamily motor protein KIF17 and mLin-10 in NMDA receptor-containing vesicle transport. Science 288, 1796–1802 (2000).

    CAS  PubMed  Google Scholar 

  81. Guillaud, L., Setou, M. & Hirokawa, N. KIF17 dynamics and regulation of NR2B trafficking in hippocampal neurons. J. Neurosci. 23, 131–140 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Chu, P. J., Rivera, J. F. & Arnold, D. B. A role for Kif17 in transport of Kv4.2. J. Biol. Chem. 281, 365–373 (2006).

    CAS  PubMed  Google Scholar 

  83. Saxton, W. M. & Hollenbeck, P. J. The axonal transport of mitochondria. J. Cell Sci. 125, 2095–2104 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Watanabe, K. et al. Networks of polarized actin filaments in the axon initial segment provide a mechanism for sorting axonal and dendritic proteins. Cell Rep. 2, 1546–1553 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Kapitein, L. C. et al. Myosin-V opposes microtubule-based cargo transport and drives directional motility on cortical actin. Curr. Biol. 23, 828–834 (2013).

    CAS  PubMed  Google Scholar 

  86. Konishi, Y. & Setou, M. Tubulin tyrosination navigates the kinesin-1 motor domain to axons. Nat. Neurosci. 12, 559–567 (2009).

    CAS  PubMed  Google Scholar 

  87. Verhey, K. J. & Gaertig, J. The tubulin code. Cell Cycle 6, 2152–2160 (2007).

    CAS  PubMed  Google Scholar 

  88. Hammond, J. W. et al. Posttranslational modifications of tubulin and the polarized transport of kinesin-1 in neurons. Mol. Biol. Cell 21, 572–583 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Kaul, N., Soppina, V. & Verhey, K. J. Effects of α-tubulin K40 acetylation and detyrosination on kinesin-1 motility in a purified system. Biophys. J. 106, 2636–2643 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Janke, C. & Bulinski, J. C. Post-translational regulation of the microtubule cytoskeleton: mechanisms and functions. Nat. Rev. Mol. Cell Biol. 12, 773–786 (2011).

    CAS  PubMed  Google Scholar 

  91. Magiera, M. M. & Janke, C. Post-translational modifications of tubulin. Curr. Biol. 24, R351–R354 (2014).

    CAS  PubMed  Google Scholar 

  92. Ludueña, R. F. A hypothesis on the origin and evolution of tubulin. Int. Rev. Cell. Mol. Biol. 302, 41–185 (2013).

    PubMed  Google Scholar 

  93. Szyk, A. et al. Molecular basis for age-dependent microtubule acetylation by tubulin acetyltransferase. Cell 157, 1405–1415 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Janke, C. The tubulin code: molecular components, readout mechanisms, and functions. J. Cell Biol. 206, 461–472 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Reed, N. A. et al. Microtubule acetylation promotes kinesin-1 binding and transport. Curr. Biol. 16, 2166–2172 (2006).

    CAS  PubMed  Google Scholar 

  96. Sirajuddin, M., Rice, L. M. & Vale, R. D. Regulation of microtubule motors by tubulin isotypes and post-translational modifications. Nat. Cell Biol. 16, 335–344 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Nakata, T., Niwa, S., Okada, Y., Perez, F. & Hirokawa, N. Preferential binding of a kinesin-1 motor to GTP-tubulin-rich microtubules underlies polarized vesicle transport. J. Cell Biol. 194, 245–255 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Morikawa, M. et al. X-Ray and Cryo-EM structures reveal mutual conformational changes of Kinesin and GTP-state microtubules upon binding. EMBO J. 34, 1270–1286 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Petersen, J. D., Kaech, S. & Banker, G. Selective microtubule-based transport of dendritic membrane proteins arises in concert with axon specification. J. Neurosci. 34, 4135–4147 (2014). This paper, which characterizes selective dendritic transport, shows that dendritically polarized vesicles reverse direction at the proximal part of the axon initial segment.

    PubMed  PubMed Central  Google Scholar 

  100. Black, M. M. & Baas, P. W. The basis of polarity in neurons. Trends Neurosci. 12, 211–214 (1989).

    CAS  PubMed  Google Scholar 

  101. Lewis, T. L., Mao, T., Svoboda, K. & Arnold, D. B. Myosin-dependent targeting of transmembrane proteins to neuronal dendrites. Nat. Neurosci. 12, 568–576 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Song, A. H. et al. A selective filter for cytoplasmic transport at the axon initial segment. Cell 136, 1148–1160 (2009).

    CAS  PubMed  Google Scholar 

  103. van Spronsen, M. et al. TRAK/Milton motor-adaptor proteins steer mitochondrial trafficking to axons and dendrites. Neuron 77, 485–502 (2013).

    CAS  PubMed  Google Scholar 

  104. Setou, M. et al. Glutamate-receptor-interacting protein GRIP1 directly steers kinesin to dendrites. Nature 417, 83–87 (2002).

    CAS  PubMed  Google Scholar 

  105. Jenkins, B., Decker, H., Bentley, M., Luisi, J. & Banker, G. A novel split kinesin assay identifies motor proteins that interact with distinct vesicle populations. J. Cell Biol. 198, 749–761 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Silverman, M. A. et al. Sorting and directed transport of membrane proteins during development of hippocampal neurons in culture. Proc. Natl Acad. Sci. USA 98, 7051–7057 (2001).

    CAS  PubMed  Google Scholar 

  107. Kuijpers, M. et al. Dynein regulator NDEL1 controls polarized cargo transport at the axon initial segment. Neuron 89, 461–471 (2016).

    CAS  PubMed  Google Scholar 

  108. Arnold, D. B. Actin and microtubule-based cytoskeletal cues direct polarized targeting of proteins in neurons. Sci. Signal. 2, pe49 (2009).

    PubMed  PubMed Central  Google Scholar 

  109. Setou, M., Hayasaka, T. & Yao, I. Axonal transport versus dendritic transport. J. Neurobiol. 58, 201–206 (2004).

    PubMed  Google Scholar 

  110. Fu, M. M. & Holzbaur, E. L. F. Integrated regulation of motor-driven organelle transport by scaffolding proteins. Trends Cell Biol. 24, 564–574 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Gibbs, K. L., Greensmith, L. & Schiavo, G. Regulation of axonal transport by protein kinases. Trends Biochem. Sci. 40, 597–610 (2015).

    CAS  PubMed  Google Scholar 

  112. Akin, E. J., Solé, L., Dib-Hajj, S. D., Waxman, S. G. & Tamkun, M. M. Preferential targeting of Nav1.6 voltage-gated Na+ channels to the axon initial segment during development. PLoS ONE 10, e0124397 (2015).

    PubMed  PubMed Central  Google Scholar 

  113. Mostov, K. E., Verges, M. & Altschuler, Y. Membrane traffic in polarized epithelial cells. Curr. Opin. Cell Biol. 12, 483–490 (2000).

    CAS  PubMed  Google Scholar 

  114. Beest, ter, M. B. A., Chapin, S. J., Avrahami, D. & Mostov, K. E. The role of syntaxins in the specificity of vesicle targeting in polarized epithelial cells. Mol. Biol. Cell 16, 5784–5792 (2005).

    Google Scholar 

  115. Barnes, A. P. & Polleux, F. Establishment of axon-dendrite polarity in developing neurons. Annu. Rev. Neurosci. 32, 347–381 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Cheng, P. L. & Poo, M. M. Early events in axon/dendrite polarization. Annu. Rev. Neurosci. 35, 181–201 (2012).

    CAS  PubMed  Google Scholar 

  117. Caceres, A., Ye, B. & Dotti, C. G. Neuronal polarity: demarcation, growth and commitment. Curr. Opin. Cell Biol. 24, 547–553 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Liu, Z., Lavis, L. D. & Betzig, E. Imaging live-cell dynamics and structure at the single-molecule level. Mol. Cell 58, 644–659 (2015).

    CAS  PubMed  Google Scholar 

  119. Heidenreich, M. & Zhang, F. Applications of CRISPR–Cas systems in neuroscience. Nat. Rev. Neurosci. 17, 36–44 (2015).

    PubMed  PubMed Central  Google Scholar 

  120. Hsu, P. D., Lander, E. S. & Zhang, F. Development and applications of CRISPR-Cas9 for genome engineering. Cell 157, 1262–1278 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Kaech, S., Huang, C.-F. & Banker, G. Short-term high-resolution imaging of developing hippocampal neurons in culture. Cold Spring Harb. Protoc. 2012, 340–343 (2012).

    PubMed  PubMed Central  Google Scholar 

  122. Kaech, S., Huang, C.-F. & Banker, G. Long-term time-lapse imaging of developing hippocampal neurons in culture. Cold Spring Harb. Protoc. 2012, 335–339 (2012).

    PubMed  PubMed Central  Google Scholar 

  123. Hayashi, K., Kawai-Hirai, R., Harada, A. & Takata, K. Inhibitory neurons from fetal rat cerebral cortex exert delayed axon formation and active migration in vitro. J. Cell Sci. 116, 4419–4428 (2003).

    CAS  PubMed  Google Scholar 

  124. Mitsui, S., Saito, M., Hayashi, K., Mori, K. & Yoshihara, Y. A novel phenylalanine-based targeting signal directs telencephalin to neuronal dendrites. J. Neurosci. 25, 1122–1131 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Rolls, M. M. Neuronal polarity in Drosophila: sorting out axons and dendrites. Dev. Neurobiol. 71, 419–429 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Rolls, M. M. & Jegla, T. J. Neuronal polarity: an evolutionary perspective. J. Exp. Biol. 218, 572–580 (2015).

    PubMed  PubMed Central  Google Scholar 

  127. Ou, C. Y. & Shen, K. Neuronal polarity in C. elegans. Dev. Neurobiol. 71, 554–566 (2011).

    PubMed  Google Scholar 

  128. Chua, J. J. E., Jahn, R. & Klopfenstein, D. R. Managing intracellular transport. Worm 2, e21564 (2013).

    PubMed  PubMed Central  Google Scholar 

  129. Sato, K., Norris, A., Sato, M. & Grant, B. D. in WormBook (ed. The C. elegans Research Community) 1–47 (2014).

    Google Scholar 

  130. Drerup, C. M. & Nechiporuk, A. V. JNK-interacting protein 3 mediates the retrograde transport of activated c-Jun N-terminal kinase and lysosomes. PLoS Genet. 9, e1003303 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Stowers, R. S., Megeath, L. J., Górska-Andrzejak, J., Meinertzhagen, I. A. & Schwarz, T. L. Axonal transport of mitochondria to synapses depends on milton, a novel Drosophila protein. Neuron 36, 1063–1077 (2002).

    CAS  PubMed  Google Scholar 

  132. Guo, X. et al. The GTPase dMiro is required for axonal transport of mitochondria to Drosophila synapses. Neuron 47, 379–393 (2005).

    CAS  PubMed  Google Scholar 

  133. Glater, E. E., Megeath, L. J., Stowers, R. S. & Schwarz, T. L. Axonal transport of mitochondria requires milton to recruit kinesin heavy chain and is light chain independent. J. Cell Biol. 173, 545–557 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Russo, G. J. et al. Drosophila Miro is required for both anterograde and retrograde axonal mitochondrial transport. J. Neurosci. 29, 5443–5455 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Nguyen, M. M. et al. γ-Tubulin controls neuronal microtubule polarity independently of Golgi outposts. Mol. Biol. Cell 25, 2039–2050 (2014).

    PubMed  PubMed Central  Google Scholar 

  136. Kern, J. V., Zhang, Y. V., Kramer, S., Brenman, J. E. & Rasse, T. M. The kinesin-3, Unc-104 regulates dendrite morphogenesis and synaptic development in Drosophila. Genetics 195, 59–72 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Klopfenstein, D. R. & Vale, R. D. The lipid binding pleckstrin homology domain in UNC-104 kinesin is necessary for synaptic vesicle transport in Caenorhabditis elegans. Mol. Biol. Cell 15, 3729–3739 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Pilling, A. D., Horiuchi, D., Lively, C. M. & Saxton, W. M. Kinesin-1 and Dynein are the primary motors for fast transport of mitochondria in Drosophila motor axons. Mol. Biol. Cell 17, 2057–2068 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Hoerndli, F. J. et al. Kinesin-1 regulates synaptic strength by mediating the delivery, removal, and redistribution of AMPA receptors. Neuron 80, 1421–1437 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Hoerndli, F. J. et al. Neuronal activity and CaMKII regulate kinesin-mediated transport of synaptic AMPARs. Neuron 86, 457–474 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Choquet, D. & Triller, A. The dynamic synapse. Neuron 80, 691–703 (2013).

    CAS  PubMed  Google Scholar 

  142. Das, S. S. & Banker, G. A. The role of protein interaction motifs in regulating the polarity and clustering of the metabotropic glutamate receptor mGluR1a. J. Neurosci. 26, 8115–8125 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Cheng, C., Glover, G., Banker, G. & Amara, S. G. A novel sorting motif in the glutamate transporter excitatory amino acid transporter 3 directs its targeting in Madin–Darby canine kidney cells and hippocampal neurons. J. Neurosci. 22, 10643–10652 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Coombs, J. S., Curtis, D. R. & Eccles, J. C. The interpretation of spike potentials of motoneurones. J. Physiol. (Lond.) 139, 198–231 (1957).

    CAS  Google Scholar 

  145. Palay, S. L., Sotelo, C., Peters, A. & Orkand, P. M. The axon hillock and the initial segment. J. Cell Biol. 38, 193–201 (1968).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Winckler, B., Forscher, P. & Mellman, I. A diffusion barrier maintains distribution of membrane proteins in polarized neurons. Nature 397, 698–701 (1999).

    CAS  PubMed  Google Scholar 

  147. Nakada, C. et al. Accumulation of anchored proteins forms membrane diffusion barriers during neuronal polarization. Nat. Cell Biol. 5, 626–632 (2003).

    CAS  PubMed  Google Scholar 

  148. Fujiwara, T., Ritchie, K., Murakoshi, H., Jacobson, K. & Kusumi, A. Phospholipids undergo hop diffusion in compartmentalized cell membrane. J. Cell Biol. 157, 1071–1081 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Jones, S. L., Korobova, F. & Svitkina, T. Axon initial segment cytoskeleton comprises a multiprotein submembranous coat containing sparse actin filaments. J. Cell Biol. 2, 89 (2014).

    Google Scholar 

  150. Hedstrom, K. L., Ogawa, Y. & Rasband, M. N. AnkyrinG is required for maintenance of the axon initial segment and neuronal polarity. J. Cell Biol. 183, 635–640 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Jenkins, P. M. et al. Giant ankyrin-G: a critical innovation in vertebrate evolution of fast and integrated neuronal signaling. Proc. Natl Acad. Sci. USA 112, 957–964 (2014). This paper shows that the loss of the axon initial segment does not disrupt selective dendritic transport.

    PubMed  Google Scholar 

  152. Sobotzik, J. M. et al. AnkyrinG is required to maintain axo-dendritic polarity in vivo. Proc. Natl Acad. Sci. USA 106, 17564–17569 (2009).

    CAS  PubMed  Google Scholar 

  153. Gallon, M. & Cullen, P. J. Retromer and sorting nexins in endosomal sorting. Biochem. Soc. Trans. 43, 33–47 (2015).

    CAS  PubMed  Google Scholar 

  154. Kardon, J. R. & Vale, R. D. Regulators of the cytoplasmic dynein motor. Nat. Rev. Mol. Cell Biol. 10, 854–865 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Hong, W. SNAREs and traffic. Biochim. Biophys. Acta 1744, 120–144 (2005).

    CAS  PubMed  Google Scholar 

  156. Mattera, R., Farías, G. G., Mardones, G. A. & Bonifacino, J. S. Co-assembly of viral envelope glycoproteins regulates their polarized sorting in neurons. PLoS Pathog. 10, e1004107 (2014).

    PubMed  PubMed Central  Google Scholar 

  157. Eiraku, M., Hirata, Y., Takeshima, H., Hirano, T. & Kengaku, M. Delta/notch-like epidermal growth factor (EGF)-related receptor, a novel EGF-like repeat-containing protein targeted to dendrites of developing and adult central nervous system neurons. J. Biol. Chem. 277, 25400–25407 (2002).

    CAS  PubMed  Google Scholar 

  158. Xu, J., Zhu, Y. & Heinemann, S. F. Identification of sequence motifs that target neuronal nicotinic receptors to dendrites and axons. J. Neurosci. 26, 9780–9793 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Rosales, C. R., Osborne, K. D., Zuccarino, G. V., Scheiffele, P. & Silverman, M. A. A cytoplasmic motif targets neuroligin-1 exclusively to dendrites of cultured hippocampal neurons. Eur. J. Neurosci. 22, 2381–2386 (2005).

    PubMed  Google Scholar 

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Acknowledgements

The work in the authors' laboratory is supported by the US National Institutes of Health (NIH MH066179). The authors thank S. Kaech for her comments on the manuscript and S. Henderson for help in creating the figures. The images in Figure 2, panels b and c, are supplied by M.B. and G.B.

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  1. The Jungers Center for Neurosciences Research, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, 97239, Oregon, USA

    Marvin Bentley & Gary Banker

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  1. Marvin Bentley
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Correspondence to Gary Banker.

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Supplementary information

Supplementary information S1 (movie)

A movie of a cultured neuron co-expressing axonal and dendritic proteins. Movie shows proteins being transported within the neuron. (M.B. and G.B., unpublished observations). (MOV 1071 kb)

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Glossary

Polarized cells

Cells composed of two distinct domains, which differ in molecular composition. Examples include epithelial cells, oocytes and neurons.

Cargoes

In the context of protein trafficking, cargoes refer to membrane proteins that must be moved from one compartment to another.

Endosomes

Intracellular organelles involved in the trafficking of proteins internalized from the plasma membrane.

Coat proteins

Protein components that bind to the cytosolic face of membranes, serving to concentrate cargoes into new vesicles and to induce bud formation. Some coat proteins form an electron-dense 'coat' that is visible by electron microscopy, hence the name.

Glycoproteins

Proteins that are post-translationally modified by the addition of sugar chains to ectodomain amino acid residues.

Tethering proteins

Also known as tethering factors. Proteins that initiate the first interaction between a vesicle and the target membrane where the vesicle will undergo fusion.

Motor adaptors

Proteins that link kinesin or dynein motors to vesicles or other cargoes.

Submembranous scaffolding proteins

Proteins that form complexes located just beneath the plasma membrane that bind to and concentrate specific sets of plasma membrane and cytosolic proteins.

Canonical sorting motifs

Sorting sequences that share a common three-dimensional structure that allows them to interact with identified binding pockets in heterotetrameric adaptor proteins.

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Bentley, M., Banker, G. The cellular mechanisms that maintain neuronal polarity. Nat Rev Neurosci 17, 611–622 (2016). https://doi.org/10.1038/nrn.2016.100

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