Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Plasma membrane expansion: a neuron's Herculean task

Key Points

  • Membrane for plasmalemmal expansion is generated through the secretory pathway, primarily in the neuron's perikaryon, and then transported as plasmalemmal precursor vesicles to the cell periphery for insertion. Numerous vesicle types are generated for export; they may be targeted directly to specific membrane domains or may follow a transcytotic pathway.

  • Certain membrane proteins are synthesized in the axonal growth cone, but how locally synthesized membrane proteins are inserted into the plasma membrane is unknown.

  • During de novo neurite outgrowth membrane insertion and expansion occur primarily at the growing tip. In synaptically connected growing neurons, however, the mechanisms and sites of membrane insertion are poorly understood.

  • Exocytotic insertion of membrane vesicles at the axonal growth cone requires exocyst and SNARE proteins, and it is regulated locally.

  • Dendrites receive plasmalemmal precursor vesicles from the perikaryon. In addition, they are capable of quasi-independent membrane synthesis through their own endoplasmic reticulum and Golgi outposts.

  • Endocytosis and membrane recycling occur during neurite outgrowth, but net membrane retrieval and degradation seem to be minor components of membrane flux.

  • Neuronal polarization, neurite outgrowth and plasmalemmal expansion are tightly linked phenomena.

  • Impaired plasmalemmal expansion and maintenance might be involved in a number of neurodegenerative disorders.

Abstract

The formation of axons and dendrites and maintenance of the neuron's vastly expanded surface require the continuous addition of new membrane. This is achieved by membrane synthesis through the secretory pathway followed by regulated vesicle fusion with the plasma membrane, typically in the distal neurite. However, it is far from simple: multiple distinct membrane carriers are used to target specific membrane domains, dendrites seem to operate semi-autonomously from the rest of the neuron, and exocytosis for membrane expansion is different from that for release of synaptic vesicles. Current knowledge of this process and its implications for neuronal development, function and repair are reviewed.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Modes of axonal growth in vivo.
Figure 2: Plasmalemmal precursor vesicles (PPVs) and glycoconjugate externalization in the growth cone.
Figure 3: Sites of synthesis and plasmalemmal insertion of membrane components in a growing polarized neuron.
Figure 4: Pulse–chase labelling of a rat hippocampal growth cone in culture.
Figure 5: A model of the regulation of plasmalemmal expansion in the growing axon.
Figure 6: Change in membrane topology during exocytosis of plasmalemmal precursor vesicles (PPVs).

Similar content being viewed by others

References

  1. Palay, S. L. & Chan-Palay, V. in Cellular Biology of Neurons (ed. Kandel, E. R.) 5–37 (American Physiological Society, Bethesda, 1977).

    Google Scholar 

  2. Bear, M. F., Connors, B. W. & Paradiso, M. A. Neuroscience: Exploring the Brain (Lippincott Williams and Wilkins, 2001).

    Google Scholar 

  3. Hughes, A. The growth of embryonic neurites; a study of cultures of chick neural tissues. J. Anat. 87, 150–162 (1953).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Zheng, Y. et al. Dynein is required for polarized dendritic transport and uniform microtubule orientation in axons. Nature Cell Biol. 10, 1172–1180 (2008).

    CAS  PubMed  Google Scholar 

  5. Bunge, M. B. Fine structure of nerve fibers and growth cones of isolated sympathetic neurons in culture. J. Cell Biol. 56, 713–735 (1973).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Pfenninger, K. H. & Friedman, L. B. Sites of plasmalemmal expansion in growth cones. Brain Res. Dev. Brain Res. 71, 181–192 (1993).

    CAS  PubMed  Google Scholar 

  7. Lockerbie, R. O., Miller, V. E. & Pfenninger, K. H. Regulated plasmalemmal expansion in nerve growth cones. J. Cell Biol. 112, 1215–1227 (1991).

    CAS  PubMed  Google Scholar 

  8. Deitch, J. S. & Banker, G. A. An electron microscopic analysis of hippocampal neurons developing in culture: early stages in the emergence of polarity. J. Neurosci. 13, 4301–4315 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Vaughn, J. E., Henrikson, C. K. & Grieshaber, J. A. A quantitative study of synapses on motor neuron dendritic growth cones in developing mouse spinal cord. J. Cell Biol. 60, 664–672 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Ostberg, A. & Norden, J. Ultrastructural study of degeneration and regeneration in the amphibian tectum. Brain Res. 168, 441–455 (1979).

    CAS  PubMed  Google Scholar 

  11. Pfenninger, K. H. et al. Regulation of membrane expansion at the nerve growth cone. J. Cell Sci. 116, 1209–1217 (2003).

    CAS  PubMed  Google Scholar 

  12. Peretti, D., Peris, L., Rosso, S., Quiroga, S. & Caceres, A. Evidence for the involvement of KIF4 in the anterograde transport of L1-containing vesicles. J. Cell Biol. 149, 141–152 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Ferreira, A., Niclas, J., Vale, R. D., Banker, G. & Kosik, K. S. Suppression of kinesin expression in cultured hippocampal neurons using antisense oligonucleotides. J. Cell Biol. 117, 595–606 (1992).

    CAS  PubMed  Google Scholar 

  14. Morfini, G., Quiroga, S., Rosa, A., Kosik, K. & Caceres, A. Suppression of KIF2 in PC12 cells alters the distribution of a growth cone nonsynaptic membrane receptor and inhibits neurite extension. J. Cell Biol. 138, 657–669 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Letourneau, P. C., Shattuck, T. A. & Ressler, A. H. “Pull” and “push” in neurite elongation: observations on the effects of different concentrations of cytochalasin B and taxol. Cell Motil. Cytoskeleton 8, 193–209 (1987).

    CAS  PubMed  Google Scholar 

  16. Giuditta, A., Kaplan, B. B., van Minnen, J., Alvarez, J. & Koenig, E. Axonal and presynaptic protein synthesis: new insights into the biology of the neuron. Trends Neurosci. 25, 400–404 (2002).

    CAS  PubMed  Google Scholar 

  17. Bassell, G. J. et al. Sorting of β-actin mRNA and protein to neurites and growth cones in culture. J. Neurosci. 18, 251–265 (1998). Demonstration of β-actin mRNA transport to, and localization of translational components in, the axonal growth cone.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Hengst, U. & Jaffrey, S. R. Function and translational regulation of mRNA in developing axons. Semin. Cell Dev. Biol. 18, 209–215 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Lin, A. C. & Holt, C. E. Local translation and directional steering in axons. Embo J. 26, 3729–3736 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Willis, D. E. & Twiss, J. L. The evolving roles of axonally synthesized proteins in regeneration. Curr. Opin. Neurobiol. 16, 111–118 (2006).

    CAS  PubMed  Google Scholar 

  21. Bi, J., Tsai, N. P., Lin, Y. P., Loh, H. H. & Wei, L. N. Axonal mRNA transport and localized translational regulation of κ-opioid receptor in primary neurons of dorsal root ganglia. Proc. Natl Acad. Sci. USA 103, 19919–19924 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Brittis, P. A., Lu, Q. & Flanagan, J. G. Axonal protein synthesis provides a mechanism for localized regulation at an intermediate target. Cell 110, 223–235 (2002). This paper demonstrated a role for local EPHA2 synthesis in axonal pathfinding.

    CAS  PubMed  Google Scholar 

  23. Negre-Aminou, P. & Pfenninger, K. H. Arachidonic acid turnover and phospholipase A2 activity in neuronal growth cones. J. Neurochem. 60, 1126–1136 (1993).

    CAS  PubMed  Google Scholar 

  24. Pfenninger, K. H. & Johnson, M. P. Membrane biogenesis in the sprouting neuron. I. Selective transfer of newly synthesized phospholipid into the growing neurite. J. Cell Biol. 97, 1038–1042 (1983).

    CAS  PubMed  Google Scholar 

  25. Blackmore, M. & Letourneau, P. C. Protein synthesis in distal axons is not required for axon growth in the embryonic spinal cord. Dev. Neurobiol. 67, 976–986 (2007).

    CAS  PubMed  Google Scholar 

  26. Sosa, L. et al. IGF-1 receptor is essential for the establishment of hippocampal neuronal polarity. Nature Neurosci. 9, 993–995 (2006).

    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. 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 

  29. 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 

  30. Garrido, J. J. et al. Identification of an axonal determinant in the C-terminus of the sodium channel Nav1.2. Embo J. 20, 5950–5961 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Tuma, P. L. & Hubbard, A. L. Transcytosis: crossing cellular barriers. Physiol. Rev. 83, 871–932 (2003).

    CAS  PubMed  Google Scholar 

  32. Yap, C. C. et al. Pathway selection to the axon depends on multiple targeting signals in NgCAM. J. Cell Sci. 121, 1514–1525 (2008). This study demonstrated transcytotic targeting of L1 in hippocampal neurons.

    CAS  PubMed  Google Scholar 

  33. 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  PubMed Central  Google Scholar 

  34. Nelson, W. J. Epithelial cell polarity from the outside looking in. News Physiol. Sci. 18, 143–146 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Small, R. K., Blank, M., Ghez, R. & Pfenninger, K. H. Components of the plasma membrane of growing axons. II. Diffusion of membrane protein complexes. J. Cell Biol. 98, 1434–1443 (1984).

    CAS  PubMed  Google Scholar 

  36. De Camilli, P. Exocytosis goes with a SNAP. Nature 364, 387–368 (1993).

    CAS  PubMed  Google Scholar 

  37. Chieregatti, E. & Meldolesi, J. Regulated exocytosis: new organelles for non-secretory purposes. Nature Rev. Mol. Cell Biol. 6, 181–187 (2005).

    CAS  Google Scholar 

  38. Craig, A. M., Wyborski, R. J. & Banker, G. Preferential addition of newly synthesized membrane protein at axonal growth cones. Nature 375, 592–594 (1995).

    CAS  PubMed  Google Scholar 

  39. Feldman, E. L., Axelrod, D., Schwartz, M., Heacock, A. M. & Agranoff, B. W. Studies on the localization of newly added membrane in growing neurites. J. Neurobiol. 12, 591–598 (1981).

    CAS  PubMed  Google Scholar 

  40. Zakharenko, S. & Popov, S. Dynamics of axonal microtubules regulate the topology of new membrane insertion into the growing neurites. J. Cell Biol. 143, 1077–1086 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Pfenninger, K. H. & Maylie-Pfenninger, M. F. Lectin labeling of sprouting neurons. II. Relative movement and appearance of glycoconjugates during plasmalemmal expansion. J. Cell Biol. 89, 547–559 (1981).

    CAS  PubMed  Google Scholar 

  42. Bray, D. Surface movements during the growth of single explanted neurons. Proc. Natl Acad. Sci. USA 65, 905–910 (1970).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Huber, A. B., Kolodkin, A. L., Ginty, D. D. & Cloutier, J. F. Signaling at the growth cone: ligand-receptor complexes and the control of axon growth and guidance. Annu. Rev. Neurosci. 26, 509–563 (2003).

    CAS  PubMed  Google Scholar 

  44. Dickson, B. J. Molecular mechanisms of axon guidance. Science 298, 1959–1964 (2002).

    CAS  PubMed  Google Scholar 

  45. Nishiyama, M. et al. Cyclic AMP/GMP-dependent modulation of Ca2+ channels sets the polarity of nerve growth-cone turning. Nature 423, 990–995 (2003).

    CAS  PubMed  Google Scholar 

  46. Laurino, L. et al. PI3K activation by IGF-1 is essential for the regulation of membrane expansion at the nerve growth cone. J. Cell Sci. 118, 3653–3662 (2005).

    CAS  PubMed  Google Scholar 

  47. Lipschutz, J. H. & Mostov, K. E. Exocytosis: the many masters of the exocyst. Curr. Biol. 12, R212–R214 (2002).

    CAS  PubMed  Google Scholar 

  48. Munson, M. & Novick, P. The exocyst defrocked, a framework of rods revealed. Nature Struct. Mol. Biol. 13, 577–581 (2006).

    CAS  Google Scholar 

  49. Murthy, M., Garza, D., Scheller, R. H. & Schwarz, T. L. Mutations in the exocyst component Sec5 disrupt neuronal membrane traffic, but neurotransmitter release persists. Neuron 37, 433–447 (2003).

    CAS  PubMed  Google Scholar 

  50. Hazuka, C. D. et al. The sec6/8 complex is located at neurite outgrowth and axonal synapse-assembly domains. J. Neurosci. 19, 1324–1334 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Vega, I. E. & Hsu, S. C. The exocyst complex associates with microtubules to mediate vesicle targeting and neurite outgrowth. J. Neurosci. 21, 3839–3848 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. du Cheyron, D. et al. Angiotensin II stimulates NHE3 activity by exocytic insertion of the transporter: role of PI 3-kinase. Kidney Int. 64, 939–949 (2003).

    CAS  PubMed  Google Scholar 

  53. Bezzerides, V. J., Ramsey, I. S., Kotecha, S., Greka, A. & Clapham, D. E. Rapid vesicular translocation and insertion of TRP channels. Nature Cell Biol. 6, 709–720 (2004).

    CAS  PubMed  Google Scholar 

  54. Cheatham, B. et al. Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation. Mol. Cell. Biol. 14, 4902–4911 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Inoue, M., Chang, L., Hwang, J., Chiang, S. H. & Saltiel, A. R. The exocyst complex is required for targeting of Glut4 to the plasma membrane by insulin. Nature 422, 629–633 (2003).

    CAS  PubMed  Google Scholar 

  56. Steiner, P. et al. Overexpression of neuronal Sec1 enhances axonal branching in hippocampal neurons. Neuroscience 113, 893–905 (2002).

    CAS  PubMed  Google Scholar 

  57. Martinez-Arca, S. et al. A common exocytotic mechanism mediates axonal and dendritic outgrowth. J. Neurosci. 21, 3830–3838 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Igarashi, M. et al. Growth cone collapse and inhibition of neurite growth by Botulinum neurotoxin C1: a t-SNARE is involved in axonal growth. J. Cell Biol. 134, 205–215 (1996).

    CAS  PubMed  Google Scholar 

  59. Osen-Sand, A. et al. Common and distinct fusion proteins in axonal growth and transmitter release. J. Comp. Neurol. 367, 222–234 (1996).

    CAS  PubMed  Google Scholar 

  60. Osen-Sand, A. et al. Inhibition of axonal growth by SNAP-25 antisense oligonucleotides in vitro and in vivo. Nature 364, 445–448 (1993).

    CAS  PubMed  Google Scholar 

  61. Hirling, H. et al. Syntaxin 13 is a developmentally regulated SNARE involved in neurite outgrowth and endosomal trafficking. Eur. J. Neurosci. 12, 1913–1923 (2000).

    CAS  PubMed  Google Scholar 

  62. Darios, F. & Davletov, B. Omega-3 and omega-6 fatty acids stimulate cell membrane expansion by acting on syntaxin 3. Nature 440, 813–817 (2006).

    CAS  PubMed  Google Scholar 

  63. Washbourne, P. et al. Genetic ablation of the t-SNARE SNAP-25 distinguishes mechanisms of neuroexocytosis. Nature Neurosci. 5, 19–26 (2002).

    CAS  PubMed  Google Scholar 

  64. Delgado-Martinez, I., Nehring, R. B. & Sorensen, J. B. Differential abilities of SNAP-25 homologs to support neuronal function. J. Neurosci. 27, 9380–9391 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Pomorski, T. & Menon, A. K. Lipid flippases and their biological functions. Cell. Mol. Life Sci. 63, 2908–2921 (2006).

    CAS  PubMed  Google Scholar 

  66. Devaux, P. F. Is lipid translocation involved during endo- and exocytosis? Biochimie 82, 497–509 (2000).

    CAS  PubMed  Google Scholar 

  67. Pfenninger, K. H. & Johnson, M. P. Nerve growth factor stimulates phospholipid methylation in growing neurites. Proc. Natl Acad. Sci. USA 78, 7797–7800 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Kamiguchi, H. & Lemmon, V. Recycling of the cell adhesion molecule L1 in axonal growth cones. J. Neurosci. 20, 3676–3686 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Diestel, S., Schaefer, D., Cremer, H. & Schmitz, B. NCAM is ubiquitylated, endocytosed and recycled in neurons. J. Cell Sci. 120, 4035–4049 (2007).

    CAS  PubMed  Google Scholar 

  70. Bonanomi, D. et al. Identification of a developmentally regulated pathway of membrane retrieval in neuronal growth cones. J. Cell Sci. 121, 3757–3769 (2008).

    CAS  PubMed  Google Scholar 

  71. Dotti, C. G., Sullivan, C. A. & Banker, G. A. The establishment of polarity by hippocampal neurons in culture. J. Neurosci. 8, 1454–1468 (1988). This classic paper describes the stages of axon versus dendrite outgrowth during neuronal differentiation.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Tucker, R. P. & Matus, A. I. Microtubule-associated proteins characteristic of embryonic brain are found in the adult mammalian retina. Dev. Biol. 130, 423–434 (1988).

    CAS  PubMed  Google Scholar 

  73. Goslin, K. & Banker, G. Rapid changes in the distribution of GAP-43 correlate with the expression of neuronal polarity during normal development and under experimental conditions. J. Cell Biol. 110, 1319–1331 (1990).

    CAS  PubMed  Google Scholar 

  74. 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 

  75. Chao, M. V. Neurotrophins and their receptors: a convergence point for many signalling pathways. Nature Rev. Neurosci. 4, 299–309 (2003).

    CAS  Google Scholar 

  76. Bonni, A. & Greenberg, M. E. Neurotrophin regulation of gene expression. Can. J. Neurol. Sci. 24, 272–283 (1997).

    CAS  PubMed  Google Scholar 

  77. Rodriguez-Boulan, E. & Powell, S. K. Polarity of epithelial and neuronal cells. Annu. Rev. Cell Biol. 8, 395–427 (1992).

    CAS  PubMed  Google Scholar 

  78. Pierce, J. P., Mayer, T. & McCarthy, J. B. Evidence for a satellite secretory pathway in neuronal dendritic spines. Curr. Biol. 11, 351–355 (2001).

    CAS  PubMed  Google Scholar 

  79. Horton, A. C. & Ehlers, M. D. Dual modes of endoplasmic reticulum-to-Golgi transport in dendrites revealed by live-cell imaging. J. Neurosci. 23, 6188–6199 (2003). This paper and reference 82 provided key evidence for the roles of Golgi outposts in dendritic vesicular trafficking and outgrowth.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Steward, O. & Schuman, E. M. Compartmentalized synthesis and degradation of proteins in neurons. Neuron 40, 347–359 (2003).

    CAS  PubMed  Google Scholar 

  81. Crino, P. B. & Eberwine, J. Molecular characterization of the dendritic growth cone: regulated mRNA transport and local protein synthesis. Neuron 17, 1173–1187 (1996).

    CAS  PubMed  Google Scholar 

  82. Horton, A. C. et al. Polarized secretory trafficking directs cargo for asymmetric dendrite growth and morphogenesis. Neuron 48, 757–771 (2005).

    CAS  PubMed  Google Scholar 

  83. Grosse, G. et al. SNAP-25 requirement for dendritic growth of hippocampal neurons. J. Neurosci. Res. 56, 539–546 (1999).

    CAS  PubMed  Google Scholar 

  84. Bisbal, M. et al. Protein kinase D regulates trafficking of dendritic membrane proteins in developing neurons. J. Neurosci. 28, 9297–9308 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Yin, D. M., Huang, Y. H., Zhu, Y. B. & Wang, Y. Both the establishment and maintenance of neuronal polarity require the activity of protein kinase D in the Golgi apparatus. J. Neurosci. 28, 8832–8843 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Ye, B. et al. Growing dendrites and axons differ in their reliance on the secretory pathway. Cell 130, 717–729 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Parton, R. G., Simons, K. & Dotti, C. G. Axonal and dendritic endocytic pathways in cultured neurons. J. Cell Biol. 119, 123–137 (1992).

    CAS  PubMed  Google Scholar 

  88. Park, M. et al. Plasticity-induced growth of dendritic spines by exocytic trafficking from recycling endosomes. Neuron 52, 817–830 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. O'Brien, J. & Unwin, N. Organization of spines on the dendrites of Purkinje cells. Proc. Natl Acad. Sci. USA 103, 1575–1580 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Parrish, J. Z., Emoto, K., Kim, M. D. & Jan, Y. N. Mechanisms that regulate establishment, maintenance, and remodeling of dendritic fields. Annu. Rev. Neurosci. 30, 399–423 (2007).

    CAS  PubMed  Google Scholar 

  91. Polleux, F., Morrow, T. & Ghosh, A. Semaphorin 3A is a chemoattractant for cortical apical dendrites. Nature 404, 567–573 (2000).

    CAS  PubMed  Google Scholar 

  92. Gomis-Ruth, S., Wierenga, C. J. & Bradke, F. Plasticity of polarization: changing dendrites into axons in neurons integrated in neuronal circuits. Curr. Biol. 18, 992–1000 (2008).

    PubMed  Google Scholar 

  93. Dotti, C. G. & Banker, G. A. Experimentally induced alteration in the polarity of developing neurons. Nature 330, 254–256 (1987).

    CAS  PubMed  Google Scholar 

  94. Arimura, N. & Kaibuchi, K. Neuronal polarity: from extracellular signals to intracellular mechanisms. Nature Rev. Neurosci. 8, 194–205 (2007).

    CAS  Google Scholar 

  95. Bisby, M. A. Dependence of GAP43 (B50, F1) transport on axonal regeneration in rat dorsal root ganglion neurons. Brain Res. 458, 157–161 (1988).

    CAS  PubMed  Google Scholar 

  96. Snider, W. D., Zhou, F. Q., Zhong, J. & Markus, A. Signaling the pathway to regeneration. Neuron 35, 13–16 (2002).

    CAS  PubMed  Google Scholar 

  97. McAllister, A. K. Dynamic aspects of CNS synapse formation. Annu. Rev. Neurosci. 30, 425–450 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Arikkath, J. & Reichardt, L. F. Cadherins and catenins at synapses: roles in synaptogenesis and synaptic plasticity. Trends Neurosci. 31, 487–494 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Schoch, S. et al. SNARE function analyzed in synaptobrevin/VAMP knockout mice. Science 294, 1117–1122 (2001).

    CAS  PubMed  Google Scholar 

  100. Gil, J. M. & Rego, A. C. Mechanisms of neurodegeneration in Huntington's disease. Eur. J. Neurosci. 27, 2803–2820 (2008).

    PubMed  Google Scholar 

  101. Szebenyi, G. et al. Neuropathogenic forms of huntingtin and androgen receptor inhibit fast axonal transport. Neuron 40, 41–52 (2003).

    CAS  PubMed  Google Scholar 

  102. Hattula, K. & Peranen, J. FIP-2, a coiled-coil protein, links Huntingtin to Rab8 and modulates cellular morphogenesis. Curr. Biol. 10, 1603–1606 (2000).

    CAS  PubMed  Google Scholar 

  103. Huber, L. A., Dupree, P. & Dotti, C. G. A deficiency of the small GTPase rab8 inhibits membrane traffic in developing neurons. Mol. Cell. Biol. 15, 918–924 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. McGuire, J. R., Rong, J., Li, S. H. & Li, X. J. Interaction of Huntingtin-associated protein-1 with kinesin light chain: implications in intracellular trafficking in neurons. J. Biol. Chem. 281, 3552–3559 (2006).

    CAS  PubMed  Google Scholar 

  105. Gauthier, L. R. et al. Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 118, 127–138 (2004).

    CAS  PubMed  Google Scholar 

  106. Engelender, S. et al. Huntingtin-associated protein 1 (HAP1) interacts with the p150Glued subunit of dynactin. Hum. Mol. Genet. 6, 2205–2212 (1997).

    CAS  PubMed  Google Scholar 

  107. Caviston, J. P., Ross, J. L., Antony, S. M., Tokito, M. & Holzbaur, E. L. Huntingtin facilitates dynein/dynactin-mediated vesicle transport. Proc. Natl Acad. Sci. USA 104, 10045–10050 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Lakkaraju, A. & Rodriguez-Boulan, E. Cell biology: caught in the traffic. Nature 448, 266–267 (2007).

    CAS  PubMed  Google Scholar 

  109. Truant, R., Atwal, R. & Burtnik, A. Hypothesis: huntingtin may function in membrane association and vesicular trafficking. Biochem. Cell Biol. 84, 912–917 (2006).

    CAS  PubMed  Google Scholar 

  110. Shy, M. E. Charcot-Marie-Tooth disease: an update. Curr. Opin. Neurol. 17, 579–585 (2004).

    CAS  PubMed  Google Scholar 

  111. Rismanchi, N., Soderblom, C., Stadler, J., Zhu, P. P. & Blackstone, C. Atlastin GTPases are required for Golgi apparatus and ER morphogenesis. Hum. Mol. Genet. 17, 1591–1604 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Zhu, P. P., Soderblom, C., Tao-Cheng, J. H., Stadler, J. & Blackstone, C. SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development. Hum. Mol. Genet. 15, 1343–1353 (2006).

    CAS  PubMed  Google Scholar 

  113. Suter, U. & Scherer, S. S. Disease mechanisms in inherited neuropathies. Nature Rev. Neurosci. 4, 714–726 (2003).

    CAS  Google Scholar 

  114. Smith, D. H., Wolf, J. A. & Meaney, D. F. A new strategy to produce sustained growth of central nervous system axons: continuous mechanical tension. Tissue Eng. 7, 131–139 (2001).

    CAS  PubMed  Google Scholar 

  115. Alder-Baerens, N., Lisman, Q., Luong, L., Pomorski, T. & Holthuis, J. C. Loss of P4 ATPases Drs2p and Dnf3p disrupts aminophospholipid transport and asymmetry in yeast post-Golgi secretory vesicles. Mol. Biol. Cell 17, 1632–1642 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Kutay, U., Ahnert-Hilger, G., Hartmann, E., Wiedenmann, B. & Rapoport, T. A. Transport route for synaptobrevin via a novel pathway of insertion into the endoplasmic reticulum membrane. Embo J. 14, 217–223 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Bonifacino, J. S. & Glick, B. S. The mechanisms of vesicle budding and fusion. Cell 116, 153–166 (2004).

    CAS  PubMed  Google Scholar 

  118. Farquhar, M. G. & Palade, G. E. The Golgi apparatus: 100 years of progress and controversy. Trends Cell Biol. 8, 2–10 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Katz, F. N. & Lodish, H. F. Transmembrane biogenesis of the vesicular stomatitis virus glycoprotein. J. Cell Biol. 80, 416–426 (1979).

    CAS  PubMed  Google Scholar 

  120. 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 

  121. Nelson, W. J. & Yeaman, C. Protein trafficking in the exocytic pathway of polarized epithelial cells. Trends Cell Biol. 11, 483–486 (2001).

    CAS  PubMed  Google Scholar 

  122. Finger, F. P. & White, J. G. Fusion and fission: membrane trafficking in animal cytokinesis. Cell 108, 727–730 (2002).

    CAS  PubMed  Google Scholar 

  123. Lecuit, T. & Wieschaus, E. Polarized insertion of new membrane from a cytoplasmic reservoir during cleavage of the Drosophila embryo. J. Cell Biol. 150, 849–860 (2000). A striking demonstration of highly polarized, specifically targeted membrane expansion in non-neuronal cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Samaj, J., Muller, J., Beck, M., Bohm, N. & Menzel, D. Vesicular trafficking, cytoskeleton and signalling in root hairs and pollen tubes. Trends Plant Sci. 11, 594–600 (2006).

    CAS  PubMed  Google Scholar 

  125. Wickner, W. & Schekman, R. Membrane fusion. Nature Struct. Mol. Biol. 15, 658–664 (2008).

    CAS  Google Scholar 

  126. Jahn, R., Lang, T. & Sudhof, T. C. Membrane fusion. Cell 112, 519–533 (2003).

    CAS  PubMed  Google Scholar 

  127. Pfenninger, K. H. & Rees, R. P. in Neuronal Recognition (ed. Barondes, S. H.) 131–178 (Plenum Press, New York and London, 1976).

    Google Scholar 

Download references

Acknowledgements

The author wishes to thank M.-F. Maylie-Pfenninger and L. Sosa for helpful discussions, and his many former and present associates for their contributions to this work. Relevant studies in the author's laboratory were supported by grants from the US National Institutes of Health and the National Science Foundation.

Author information

Authors and Affiliations

Authors

Related links

Related links

DATABASES

OMIM

Huntington's disease

Glossary

Growth cone

The terminally enlarged, amoeboid tip of a neurite.

Perikaryon

The portion of the neuron that surrounds the nucleus and excludes the neurites. Also referred to as the cell body.

Microtubule plus end

Microtubules are polarized structures, and the plus end is the end at which polymerization predominantly occurs. By contrast, disassembly predominates at the minus end. In axons, microtubules are oriented so that the plus ends point towards the growth cone or presynaptic terminal.

Trans-Golgi network

The last stage of the Golgi complex, where sorting of components and vesicle formation take place.

Freeze fracture

A preparative method for electron microscopy that involves rapidly freezing and fracturing the biological sample and then shadow casting it with a metal vapour to generate a replica of the fracture face. Ultrastructural analysis of the replica reveals structures in the lipid bilayer, such as intramembrane particles, that are thought to represent membrane-protein complexes.

Moving-boundary system

A system that expands with time so that diffusion in it never reaches equilibrium, as long as expansion (in this case neurite growth) exceeds the diffusion rate.

Lectin

A protein that recognizes and binds to specific oligosaccharide sequences.

Excimer

Very transient dimers of fluorescent molecules, one of which is in an excited state. Emission during return to the ground state is of lower energy (red shift) than that of excited monomers. The term is a contraction of 'excited dimer'.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pfenninger, K. Plasma membrane expansion: a neuron's Herculean task. Nat Rev Neurosci 10, 251–261 (2009). https://doi.org/10.1038/nrn2593

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn2593

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing