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:

Polysialic acid in the plasticity of the developing and adult vertebrate nervous system

Nature Reviews Neuroscience volume 9, pages 26–35 (2008)Cite this article

Key Points

  • Polysialic acid (PSA) is a cell-surface glycan that has an enormous hydrated volume that serves to modulate the distance between cells and, thereby, the strength of their interaction.

  • PSA synthesis is accomplished by a single enzyme activity produced by either of two polysialyltransferases, and occurs primarily on NCAM. Mutation of the transferases causes lethality, possibly because of alterations in cell differentiation, as well as a number of more subtle changes in brain architecture and function.

  • PSA regulation has direct effects on several cellular mechanisms that underlie the formation of the vertebrate nervous system, most conspicuously in the migration and differentiation of progenitor cells, the growth and targeting of axons and the establishment of sensory-dependent neural circuitry.

  • In the adult CNS, PSA is involved in a number of plasticity-related responses, including changes in circadian and hormonal patterns, adaptations to pain and stress, and aspects of learning and memory.

  • Changes in PSA levels are associated with a variety of neuropathological conditions, and might reflect either a causative influence or a response to the defect.

  • The ability of PSA to increase the plasticity of neural cells is being exploited to improve the repair of adult CNS tissue. The engineered introduction of PSA has been shown to improve both axon regeneration and the recruitment of progenitor cells.

Abstract

Polysialic acid (PSA) is a cell-surface glycan with an enormous hydrated volume that serves to modulate the distance between cells. This regulation has direct effects on several cellular mechanisms that underlie the formation of the vertebrate nervous system, most conspicuously in the migration and differentiation of progenitor cells and the growth and targeting of axons. PSA is also involved in a number of plasticity-related responses in the adult CNS, including changes in circadian and hormonal patterns, adaptations to pain and stress, and aspects of learning and memory. The ability of PSA to increase the plasticity of neural cells is being exploited to improve the repair of adult CNS tissue.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: The steric role of PSA at the cell surface.
Figure 2: Summary of the roles of PSA in the nervous system.
Figure 3: Developmental events that illustrate 'permissive' and 'insulative' roles for PSA.
Figure 4: Effects of engineered PSA expression on neural tissue repair.

Similar content being viewed by others

References

  1. Finne, J. Occurrence of unique polysialosyl carbohydrate units in glycoproteins of developing brain. J. Biol. Chem. 257, 11966–11970 (1982). This study reported the discovery of PSA in vertebrates.

    CAS  PubMed  Google Scholar 

  2. Hoffman, S. et al. Chemical characterization of a neural cell adhesion molecule purified from embryonic brain membranes. J. Biol. Chem. 257, 7720–7729 (1982).

    CAS  PubMed  Google Scholar 

  3. Finne, J., Finne, U., Deagostini-Bazin, H. & Goridis, C. Occurrence of α2–8 linked polysialosyl units in a neural cell adhesion molecule. Biochem. Biophys. Res. Commun. 112, 482–487 (1983).

    CAS  PubMed  Google Scholar 

  4. Cunningham, B. A., Hoffman, S., Rutishauser, U., Hemperly, J. J. & Edelman, G. M. Molecular topography of the neural cell adhesion molecule N-CAM: surface orientation and location of sialic acid-rich and binding regions. Proc. Natl Acad. Sci. USA 80, 3116–3120 (1983).

    CAS  PubMed  Google Scholar 

  5. Sadoul, R., Hirn, M., Deagostini-Bazin, H., Rougon, G. & Goridis, C. Adult and embryonic mouse neural cell adhesion molecules have different binding properties. Nature 304, 347–349 (1983). This report and reference 4 demonstrated that PSA can downregulate cell adhesion.

    CAS  PubMed  Google Scholar 

  6. Vimr, E. R., McCoy, R. D., Vollger, H. F., Wilkison, N. C. & Troy, F. A. Use of prokaryotic-derived probes to identify poly(sialic acid) in neonatal neuronal membranes. Proc. Natl Acad. Sci. USA 81, 1971–1975 (1984). This paper described the use of a phage-derived, PSA-specific endoneuraminidase, which made definitive functional studies of PSA possible.

    CAS  PubMed  Google Scholar 

  7. Rutishauser, U., Watanabe, M., Silver, J., Troy, F. A. & Vimr, E. R. Specific alteration of NCAM-mediated cell adhesion by an endoneuraminidase. J. Cell Biol. 101, 1842–1849 (1985).

    CAS  PubMed  Google Scholar 

  8. Rutishauser, U., Acheson, A., Hall, A. K., Mann, D. M. & Sunshine, J. The neural cell adhesion molecule (NCAM) as a regulator of cell-cell interactions. Science 240, 53–57 (1988).

    CAS  PubMed  Google Scholar 

  9. Rutishauser, U. Polysialic acid at the cell surface: biophysics in service of cell interactions and tissue plasticity. J. Cell. Biochem. 70, 304–312 (1998). This article proposed that PSA can act as a global regulator of cell interactions through its steric properties at the cell surface.

    CAS  PubMed  Google Scholar 

  10. Johnson, C. P., Fujimoto, I., Rutishauser, U. & Leckband, D. E. Direct evidence that neural cell adhesion molecule (NCAM) polysialylation increases intermembrane repulsion and abrogates adhesion. J. Biol. Chem. 280, 137–145 (2005). This study provided direct biophysical evidence that PSA regulates membrane–membrane distance.

    CAS  PubMed  Google Scholar 

  11. Fujimoto, I., Bruses, J. L. & Rutishauser, U. Regulation of cell adhesion by polysialic acid. Effects on cadherin, immunoglobulin cell adhesion molecule, and integrin function and independence from neural cell adhesion molecule binding or signaling activity. J. Biol. Chem. 276, 31745–31751 (2001).

    CAS  PubMed  Google Scholar 

  12. Eckhardt, M. et al. Molecular characterization of eukaryotic polysialyltransferase-1. Nature 373, 715–718 (1995). This study, together with references 13–15, identified PST and STX as the polysialyltransferases responsible for PSA synthesis in vertebrates.

    CAS  PubMed  Google Scholar 

  13. Kojima, N., Yoshida, Y., Kurosawa, N., Lee, Y. C. & Tsuji, S. Enzymatic activity of a developmentally regulated member of the sialyltransferase family (STX): evidence for α2,8-sialyltransferase activity toward N-linked oligosaccharides. FEBS Lett. 360, 1–4 (1995).

    CAS  PubMed  Google Scholar 

  14. Nakayama, J., Fukuda, M. N., Fredette, B., Ranscht, B. & Fukuda, M. Expression cloning of a human polysialyltransferase that forms the polysialylated neural cell adhesion molecule present in embryonic brain. Proc. Natl Acad. Sci. USA 92, 7031–7035 (1995).

    CAS  PubMed  Google Scholar 

  15. Scheidegger, E. P., Sternberg, L. R., Roth, J. & Lowe, J. B. A human STX cDNA confers polysialic acid expression in mammalian cells. J. Biol. Chem. 270, 22685–22688 (1995).

    CAS  PubMed  Google Scholar 

  16. Livingston, B. D., Jacobs, J. L., Glick, M. C. & Troy, F. A. Extended polysialic acid chains (n greater than 55) in glycoproteins from human neuroblastoma cells. J. Biol. Chem. 263, 9443–9448 (1988).

    CAS  PubMed  Google Scholar 

  17. Oka, S., Bruses, J. L., Nelson, R. W. & Rutishauser, U. Properties and developmental regulation of polysialyltransferase activity in the chicken embryo brain. J. Biol. Chem. 270, 19357–19363 (1995).

    CAS  PubMed  Google Scholar 

  18. Nelson, R. W., Bates, P. A. & Rutishauser, U. Protein determinants for specific polysialylation of the neural cell adhesion molecule. J. Biol. Chem. 270, 17171–17179 (1995).

    CAS  PubMed  Google Scholar 

  19. Mendiratta, S. S. et al. A novel α-helix in the first fibronectin type III repeat of the neural cell adhesion molecule is critical for N-glycan polysialylation. J. Biol. Chem. 281, 36052–36059 (2006).

    CAS  PubMed  Google Scholar 

  20. Mendiratta, S. S., Sekulic, N., Lavie, A. & Colley, K. J. Specific amino acids in the first fibronectin type III repeat of the neural cell adhesion molecule play a role in its recognition and polysialylation by the polysialyltransferase ST8Sia IV/PST. J. Biol. Chem. 280, 32340–32348 (2005). Together with references 18 and 19, this report demonstrated the molecular basis for the specific polysialylation of NCAM.

    CAS  PubMed  Google Scholar 

  21. James, W. M. & Agnew, W. S. Multiple oligosaccharide chains in the voltage-sensitive Na channel from Electrophorus electricus: evidence for α-2,8-linked polysialic acid. Biochem. Biophys. Res. Commun. 148, 817–826 (1987).

    CAS  PubMed  Google Scholar 

  22. Curreli, S., Arany, Z., Gerardy-Schahn, R., Mann, D. & Stamatos, N. M. Polysialylated neuropilin-2 is expressed on the surface of human dendritic cells and modulates dendritic cell-T lymphocyte interactions. J. Biol. Chem. 42, 30346–30356 (2007).

    Google Scholar 

  23. Angata, K. & Fukuda, M. Polysialyltransferases: major players in polysialic acid synthesis on the neural cell adhesion molecule. Biochimie 85, 195–206 (2003).

    CAS  PubMed  Google Scholar 

  24. Angata, K. et al. Sialyltransferase ST8Sia-II assembles a subset of polysialic acid that directs hippocampal axonal targeting and promotes fear behavior. J. Biol. Chem. 279, 32603–32613 (2004).

    CAS  PubMed  Google Scholar 

  25. Angata, K. et al. Human STX polysialyltransferase forms the embryonic form of the neural cell adhesion molecule. Tissue-specific expression, neurite outgrowth, and chromosomal localization in comparison with another polysialyltransferase, PST. J. Biol. Chem. 272, 7182–7190 (1997).

    CAS  PubMed  Google Scholar 

  26. Angata, K., Suzuki, M. & Fukuda, M. Differential and cooperative polysialylation of the neural cell adhesion molecule by two polysialyltransferases, PST and STX. J. Biol. Chem. 273, 28524–28532 (1998).

    CAS  PubMed  Google Scholar 

  27. Eckhardt, M. et al. Mice deficient in the polysialyltransferase ST8SiaIV/PST-1 allow discrimination of the roles of neural cell adhesion molecule protein and polysialic acid in neural development and synaptic plasticity. J. Neurosci. 20, 5234–5244 (2000).

    CAS  PubMed  Google Scholar 

  28. Galuska, S. P. et al. Polysialic acid profiles of mice expressing variant allelic combinations of the polysialyltransferases ST8SiaII and ST8SiaIV. J. Biol. Chem. 281, 31605–31615 (2006).

    CAS  PubMed  Google Scholar 

  29. Kojima, N., Tachida, Y. & Tsuji, S. Two polysialic acid synthases, mouse ST8Sia II and IV, synthesize different degrees of polysialic acids on different substrate glycoproteins in mouse neuroblastoma Neuro2a cells. J. Biochem. (Tokyo) 122, 1265–1273 (1997).

    CAS  Google Scholar 

  30. Marx, M., Rivera-Milla, E., Stummeyer, K., Gerardy-Schahn, R. & Bastmeyer, M. Divergent evolution of the vertebrate polysialyltransferase Stx and Pst genes revealed by fish-to-mammal comparison. Dev. Biol. 306, 560–571 (2007).

    CAS  PubMed  Google Scholar 

  31. Bruses, J. L. & Rutishauser, U. Regulation of neural cell adhesion molecule polysialylation: evidence for nontranscriptional control and sensitivity to an intracellular pool of calcium. J. Cell Biol. 140, 1177–1186 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Hinkle, C. L., Diestel, S., Lieberman, J. & Maness, P. F. Metalloprotease-induced ectodomain shedding of neural cell adhesion molecule (NCAM). J. Neurobiol. 66, 1378–1395 (2006).

    CAS  PubMed  Google Scholar 

  33. Bouzioukh, F., Tell, F., Jean, A. & Rougon, G. NMDA receptor and nitric oxide synthase activation regulate polysialylated neural cell adhesion molecule expression in adult brainstem synapses. J. Neurosci. 21, 4721–4730 (2001).

    CAS  PubMed  Google Scholar 

  34. Tang, J., Rutishauser, U. & Landmesser, L. Polysialic acid regulates growth cone behavior during sorting of motor axons in the plexus region. Neuron 13, 405–414 (1994). This study demonstrated a permissive mode of action for PSA in regulating the behaviour of neuronal growth cones during axon pathfinding.

    CAS  PubMed  Google Scholar 

  35. El Maarouf, A. & Rutishauser, U. Removal of polysialic acid induces aberrant pathways, synaptic vesicle distribution, and terminal arborization of retinotectal axons. J. Comp. Neurol. 460, 203–211 (2003).

    CAS  PubMed  Google Scholar 

  36. Seki, T. & Rutishauser, U. Removal of polysialic acid-neural cell adhesion molecule induces aberrant mossy fiber innervation and ectopic synaptogenesis in the hippocampus. J. Neurosci. 18, 3757–3766 (1998). This study demonstrated an insulative mode of action for PSA in regulating the interactions of axons with complex targets.

    CAS  PubMed  Google Scholar 

  37. Bruses, J. L. & Rutishauser, U. Roles, regulation, and mechanism of polysialic acid function during neural development. Biochimie 83, 635–643 (2001).

    CAS  PubMed  Google Scholar 

  38. Rutishauser, U. & Landmesser, L. Polysialic acid in the vertebrate nervous system: a promoter of plasticity in cell-cell interactions. Trends Neurosci. 19, 422–427 (1996).

    CAS  PubMed  Google Scholar 

  39. Ono, K., Tomasiewicz, H., Magnuson, T. & Rutishauser, U. N-CAM mutation inhibits tangential neuronal migration and is phenocopied by enzymatic removal of polysialic acid. Neuron 13, 595–609 (1994). This study documented the ability of PSA to promote cell migration.

    CAS  PubMed  Google Scholar 

  40. Hu, H., Tomasiewicz, H., Magnuson, T. & Rutishauser, U. The role of polysialic acid in migration of olfactory bulb interneuron precursors in the subventricular zone. Neuron 16, 735–743 (1996).

    CAS  PubMed  Google Scholar 

  41. Murakami, S., Seki, T., Rutishauser, U. & Arai, Y. Enzymatic removal of polysialic acid from neural cell adhesion molecule perturbs the migration route of luteinizing hormone-releasing hormone neurons in the developing chick forebrain. J. Comp. Neurol. 420, 171–181 (2000).

    CAS  PubMed  Google Scholar 

  42. Seki, T., Namba, T., Mochizuki, H. & Onodera, M. Clustering, migration, and neurite formation of neural precursor cells in the adult rat hippocampus. J. Comp. Neurol. 502, 275–290 (2007).

    CAS  PubMed  Google Scholar 

  43. Barral-Moran, M. J. et al. Oligodendrocyte progenitor migration in response to injury of glial monolayers requires the polysialic neural cell-adhesion molecule. J. Neurosci. Res. 72, 679–690 (2003).

    CAS  PubMed  Google Scholar 

  44. Landmesser, L., Dahm, L., Tang, J. C. & Rutishauser, U. Polysialic acid as a regulator of intramuscular nerve branching during embryonic development. Neuron 4, 655–667 (1990).

    CAS  PubMed  Google Scholar 

  45. Tang, J., Landmesser, L. & Rutishauser, U. Polysialic acid influences specific pathfinding by avian motoneurons. Neuron 8, 1031–1044 (1992).

    CAS  PubMed  Google Scholar 

  46. Yin, X., Watanabe, M. & Rutishauser, U. Effect of polysialic acid on the behavior of retinal ganglion cell axons during growth into the optic tract and tectum. Development 121, 3439–3446 (1995).

    CAS  PubMed  Google Scholar 

  47. Bruses, J. L., Chauvet, N., Rubio, M. E. & Rutishauser, U. Polysialic acid and the formation of oculomotor synapses on chick ciliary neurons. J. Comp. Neurol. 446, 244–256 (2002).

    CAS  PubMed  Google Scholar 

  48. Bruses, J. L., Oka, S. & Rutishauser, U. NCAM-associated polysialic acid on ciliary ganglion neurons is regulated by polysialytransferase levels and interaction with muscle. J. Neurosci. 15, 8310–8319 (1995).

    CAS  PubMed  Google Scholar 

  49. Petridis, A. K., El-Maarouf, A. & Rutishauser, U. Polysialic acid regulates cell contact-dependent neuronal differentiation of progenitor cells from the subventricular zone. Dev. Dyn. 230, 675–684 (2004). This report provided evidence that PSA can suppress the differentiation of neural progenitors.

    CAS  PubMed  Google Scholar 

  50. Seidenfaden, R., Krauter, A., Schertzinger, F., Gerardy-Schahn, R. & Hildebrandt, H. Polysialic acid directs tumor cell growth by controlling heterophilic neural cell adhesion molecule interactions. Mol. Cell. Biol. 23, 5908–5918 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Weinhold, B. et al. Genetic ablation of polysialic acid causes severe neurodevelopmental defects rescued by deletion of the neural cell adhesion molecule. J. Biol. Chem. 280, 42971–42977 (2005). This study and reference 52 mutated both the PST- and the STX-encoding gene to obtain an embryonic-lethal phenotype. Together with the NCAM gene mutation carried out in reference 53, these mutations illustrated distinct roles for PSA, NCAM and the two polysialyltransferases.

    CAS  PubMed  Google Scholar 

  52. Angata, K. et al. Polysialic acid-directed migration and differentiation of neural precursors are essential for mouse brain development. Mol. Cell. Biol. 27, 6659–6668 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Cremer, H. et al. Inactivation of the N-CAM gene in mice results in size reduction of the olfactory bulb and deficits in spatial learning. Nature 367, 455–459 (1994).

    CAS  Google Scholar 

  54. Burgess, A. & Aubert, I. Polysialic acid limits choline acetyltransferase activity induced by brain-derived neurotrophic factor. J. Neurochem. 99, 797–806 (2006).

    CAS  PubMed  Google Scholar 

  55. Gascon, E., Vutskits, L., Jenny, B., Durbec, P. & Kiss, J. Z. PSA-NCAM in postnatally generated immature neurons of the olfactory bulb: a crucial role in regulating p75 expression and cell survival. Development 134, 1181–1190 (2007).

    CAS  PubMed  Google Scholar 

  56. Di Cristo, G. et al. Activity-dependent down regulation of PSA-NCAM promotes maturation of GABAergic innervation and onset of critical period plasticity in visual cortex. Nature Neurosci. (in the press). The ability of PSA to regulate activity-dependent changes in neural circuitry is established in this study.

  57. Franceschini, I. et al. Migrating and myelinating potential of neural precursors engineered to overexpress PSA-NCAM. Mol. Cell. Neurosci. 27, 151–162 (2004).

    CAS  PubMed  Google Scholar 

  58. Fewou, S. N., Ramakrishnan, H., Bussow, H., Gieselmann, V. & Eckhardt, M. Down-regulation of polysialic acid is required for efficient myelin formation. J. Biol. Chem. 282, 16700–16711 (2007).

    CAS  PubMed  Google Scholar 

  59. Charles, P. et al. Re-expression of PSA-NCAM by demyelinated axons: an inhibitor of remyelination in multiple sclerosis? Brain 125, 1972–1979 (2002).

    PubMed  Google Scholar 

  60. Rousselot, P., Lois, C. & Alvarez-Buylla, A. Embryonic (PSA) N-CAM reveals chains of migrating neuroblasts between the lateral ventricle and the olfactory bulb of adult mice. J. Comp. Neurol. 351, 51–61 (1995).

    CAS  PubMed  Google Scholar 

  61. Seki, T. & Arai, Y. The persistent expression of a highly polysialylated NCAM in the dentate gyrus of the adult rat. Neurosci. Res. 12, 503–513 (1991).

    CAS  PubMed  Google Scholar 

  62. Bonfanti, L. PSA-NCAM in mammalian structural plasticity and neurogenesis. Prog. Neurobiol. 80, 129–164 (2006).

    CAS  PubMed  Google Scholar 

  63. Seki, T. & Arai, Y. Distribution and possible roles of the highly polysialylated neural cell adhesion molecule (NCAM-H) in the developing and adult central nervous system. Neurosci. Res. 17, 265–290 (1993).

    CAS  PubMed  Google Scholar 

  64. Theodosis, D. T., Rougon, G. & Poulain, D. A. Retention of embryonic features by an adult neuronal system capable of plasticity: polysialylated neural cell adhesion molecule in the hypothalamo-neurohypophysial system. Proc. Natl Acad. Sci. USA 88, 5494–5498 (1991).

    CAS  PubMed  Google Scholar 

  65. Kaur, G., Heera, P. K. & Srivastava, L. K. Neuroendocrine plasticity in GnRH release during rat estrous cycle: correlation with molecular markers of synaptic remodeling. Brain Res. 954, 21–31 (2002).

    CAS  PubMed  Google Scholar 

  66. Hoyk, Z., Parducz, A. & Theodosis, D. T. The highly sialylated isoform of the neural cell adhesion molecule is required for estradiol-induced morphological synaptic plasticity in the adult arcuate nucleus. Eur. J. Neurosci. 13, 649–656 (2001). This report documented the effects of PSA on the hormone-dependent morphology of synapses in the CNS.

    CAS  PubMed  Google Scholar 

  67. Nothias, F., Vernier, P., von Boxberg, Y., Mirman, S. & Vincent, J. D. Modulation of NCAM polysialylation is associated with morphofunctional modifications in the hypothalamo-neurohypophysial system during lactation. Eur. J. Neurosci. 9, 1553–1565 (1997).

    CAS  PubMed  Google Scholar 

  68. Theodosis, D. T., Bonhomme, R., Vitiello, S., Rougon, G. & Poulain, D. A. Cell surface expression of polysialic acid on NCAM is a prerequisite for activity-dependent morphological neuronal and glial plasticity. J. Neurosci. 19, 10228–10236 (1999).

    CAS  PubMed  Google Scholar 

  69. Monlezun, S., Ouali, S., Poulain, D. A. & Theodosis, D. T. Polysialic acid is required for active phases of morphological plasticity of neurosecretory axons and their glia. Mol. Cell. Neurosci. 29, 516–524 (2005).

    CAS  PubMed  Google Scholar 

  70. Glass, J. D. et al. Dynamic regulation of polysialylated neural cell adhesion molecule in the suprachiasmatic nucleus. Neuroscience 117, 203–211 (2003).

    CAS  PubMed  Google Scholar 

  71. Glass, J. D. et al. Polysialylated neural cell adhesion molecule modulates photic signaling in the mouse suprachiasmatic nucleus. Neurosci. Lett. 280, 207–210 (2000).

    CAS  PubMed  Google Scholar 

  72. Prosser, R. A., Rutishauser, U., Ungers, G., Fedorkova, L. & Glass, J. D. Intrinsic role of polysialylated neural cell adhesion molecule in photic phase resetting of the mammalian circadian clock. J. Neurosci. 23, 652–658 (2003).

    CAS  PubMed  Google Scholar 

  73. Fedorkova, L., Rutishauser, U., Prosser, R., Shen, H. & Glass, J. D. Removal of polysialic acid from the SCN potentiates nonphotic circadian phase resetting. Physiol. Behav. 77, 361–369 (2002).

    CAS  PubMed  Google Scholar 

  74. El Maarouf, A., Kolesnikov, Y., Pasternak, G. & Rutishauser, U. Polysialic acid-induced plasticity reduces neuropathic insult to the central nervous system. Proc. Natl Acad. Sci. USA 102, 11516–11520 (2005). This study presented evidence that the presence of PSA can allow the modification or uncoupling of spinal cord synapses in response to chronic pain.

    CAS  PubMed  Google Scholar 

  75. Duveau, V., Arthaud, S., Rougier, A. & Le Gal La Salle, G. Polysialylation of NCAM is upregulated by hyperthermia and participates in heat shock preconditioning-induced neuroprotection. Neurobiol. Dis. 26, 385–395 (2007).

    CAS  PubMed  Google Scholar 

  76. Becker, C. G. et al. The polysialic acid modification of the neural cell adhesion molecule is involved in spatial learning and hippocampal long-term potentiation. J. Neurosci. Res. 45, 143–152 (1996). This report documented that specific pertubation of PSA can affect learning and memory.

    CAS  PubMed  Google Scholar 

  77. Cremer, H. et al. PSA-NCAM: an important regulator of hippocampal plasticity. Int. J. Dev. Neurosci. 18, 213–220 (2000).

    CAS  PubMed  Google Scholar 

  78. Dityatev, A. et al. Polysialylated neural cell adhesion molecule promotes remodeling and formation of hippocampal synapses. J. Neurosci. 24, 9372–9382 (2004).

    CAS  PubMed  Google Scholar 

  79. Doyle, E., Nolan, P. M., Bell, R. & Regan, C. M. Hippocampal NCAM180 transiently increases sialylation during the acquisition and consolidation of a passive avoidance response in the adult rat. J. Neurosci. Res. 31, 513–523 (1992). This study provided the first evidence that PSA function is associated with learning and memory.

    CAS  PubMed  Google Scholar 

  80. Fox, G. B., O'Connell, A. W., Murphy, K. J. & Regan, C. M. Memory consolidation induces a transient and time-dependent increase in the frequency of neural cell adhesion molecule polysialylated cells in the adult rat hippocampus. J. Neurochem. 65, 2796–2799 (1995).

    CAS  PubMed  Google Scholar 

  81. Lopez-Fernandez, M. A. et al. Upregulation of polysialylated neural cell adhesion molecule in the dorsal hippocampus after contextual fear conditioning is involved in long-term memory formation. J. Neurosci. 27, 4552–4561 (2007).

    CAS  PubMed  Google Scholar 

  82. Markram, K., Gerardy-Schahn, R. & Sandi, C. Selective learning and memory impairments in mice deficient for polysialylated NCAM in adulthood. Neuroscience 144, 788–796 (2007).

    CAS  PubMed  Google Scholar 

  83. Nacher, J., Pham, K., Gil-Fernandez, V. & McEwen, B. S. Chronic restraint stress and chronic corticosterone treatment modulate differentially the expression of molecules related to structural plasticity in the adult rat piriform cortex. Neuroscience 126, 503–509 (2004).

    CAS  PubMed  Google Scholar 

  84. O'Connell, A. W. et al. Spatial learning activates neural cell adhesion molecule polysialylation in a corticohippocampal pathway within the medial temporal lobe. J. Neurochem. 68, 2538–2546 (1997).

    CAS  PubMed  Google Scholar 

  85. Pham, K., Nacher, J., Hof, P. R. & McEwen, B. S. Repeated restraint stress suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult rat dentate gyrus. Eur. J. Neurosci. 17, 879–886 (2003). This study demonstrated that chronic stress can modulate PSA levels in the CNS.

    PubMed  Google Scholar 

  86. Senkov, O. et al. Polysialylated neural cell adhesion molecule is involved in induction of long-term potentiation and memory acquisition and consolidation in a fear-conditioning paradigm. J. Neurosci. 26, 10888–109898 (2006).

    CAS  PubMed  Google Scholar 

  87. Varea, E. et al. Chronic fluoxetine treatment increases the expression of PSA-NCAM in the medial prefrontal cortex. Neuropsychopharmacology 32, 803–812 (2007).

    CAS  PubMed  Google Scholar 

  88. Sandi, C. Stress, cognitive impairment and cell adhesion molecules. Nature Rev. Neurosci. 5, 917–930 (2004).

    CAS  Google Scholar 

  89. El Maarouf, A. & Rutishauser, U. in Neuroglycobiology (eds Fukuda, M., Rutishauser, U. & Schnaar, R. L.) 39–57 (Oxford Univ. Press, London, 2005).

    Google Scholar 

  90. Mikkonen, M., Soininen, H., Tapiola, T., Alafuzoff, I. & Miettinen, R. Hippocampal plasticity in Alzheimer's disease: changes in highly polysialylated NCAM immunoreactivity in the hippocampal formation. Eur. J. Neurosci. 11, 1754–1764 (1999).

    CAS  PubMed  Google Scholar 

  91. Barbeau, D., Liang, J. J., Robitaille, Y., Quirion, R. & Srivastava, L. K. Decreased expression of the embryonic form of the neural cell adhesion molecule in schizophrenic brains. Proc. Natl Acad. Sci. USA 92, 2785–2789 (1995).

    CAS  PubMed  Google Scholar 

  92. Mikkonen, M. et al. Remodeling of neuronal circuitries in human temporal lobe epilepsy: increased expression of highly polysialylated neural cell adhesion molecule in the hippocampus and the entorhinal cortex. Ann. Neurol. 44, 923–934 (1998).

    CAS  PubMed  Google Scholar 

  93. Vicente, A. M. et al. NCAM and schizophrenia: genetic studies. Mol. Psychiatry 65–69 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Tao, R. et al. Positive association between SIAT8B and schizophrenia in the Chinese Han population. Schizophr. Res. 90, 108–114 (2007).

    PubMed  Google Scholar 

  95. Franceschini, I. et al. Polysialyltransferase ST8Sia II (STX) polysialylates all of the major isoforms of NCAM and facilitates neurite outgrowth. Glycobiology 11, 231–239 (2001).

    CAS  PubMed  Google Scholar 

  96. Aubert, I., Ridet, J. L., Schachner, M., Rougon, G. & Gage, F. H. Expression of L1 and PSA during sprouting and regeneration in the adult hippocampal formation. J. Comp. Neurol. 399, 1–19 (1998).

    CAS  PubMed  Google Scholar 

  97. Dusart, I., Morel, M. P., Wehrle, R. & Sotelo, C. Late axonal sprouting of injured Purkinje cells and its temporal correlation with permissive changes in the glial scar. J. Comp. Neurol. 408, 399–418 (1999).

    CAS  PubMed  Google Scholar 

  98. Camand, E., Morel, M. P., Faissner, A., Sotelo, C. & Dusart, I. Long-term changes in the molecular composition of the glial scar and progressive increase of serotoninergic fibre sprouting after hemisection of the mouse spinal cord. Eur. J. Neurosci. 20, 1161–1176 (2004).

    PubMed  Google Scholar 

  99. El Maarouf, A., Petridis, A. K. & Rutishauser, U. Use of polysialic acid in repair of the central nervous system. Proc. Natl Acad. Sci. USA 103, 16989–16994 (2006). This study illustrated the potential for the use of engineered PSA in the CNS to promote the repair of damaged tissue and axonal pathways.

    CAS  PubMed  Google Scholar 

  100. Zhang, Y. et al. Induced expression of polysialic acid in the spinal cord promotes regeneration of sensory axons. Mol. Cell. Neurosci. 35, 109–119 (2007).

    CAS  PubMed  Google Scholar 

  101. Zhang, Y. et al. Lentiviral-mediated expression of polysialic acid in spinal cord and conditioning lesion promote regeneration of sensory axons into spinal cord. Mol. Ther. 15, 1796–1804 (2007).

    CAS  PubMed  Google Scholar 

  102. Papastefanaki, F. et al. Grafts of Schwann cells engineered to express PSA-NCAM promote functional recovery after spinal cord injury. Brain 130, 2159–2174 (2007).

    PubMed  Google Scholar 

  103. Zhang, Y., Zhang, X., Yeh, J., Richardson, P. & Bo, X. Engineered expression of polysialic acid enhances Purkinje cell axonal regeneration in L1/GAP-43 double transgenic mice. Eur. J. Neurosci. 25, 351–361 (2007). Together with reference 102, this study showed that grafted Schwann cells with engineered PSA can be used to promote axon regeneration.

    CAS  PubMed  Google Scholar 

  104. Franz, C. K., Rutishauser, U. & Rafuse, V. F. Polysialylated neural cell adhesion molecule is necessary for selective targeting of regenerating motor neurons. J. Neurosci. 25, 2081–2091 (2005).

    CAS  PubMed  Google Scholar 

  105. Torregrossa, P. et al. Selection of poly-α2,8-sialic acid mimotopes from a random phage peptide library and analysis of their bioactivity. J. Biol. Chem. 279, 30707–30714 (2004).

    CAS  PubMed  Google Scholar 

  106. Cho, J. W. & Troy, F. A. II., Polysialic acid engineering: synthesis of polysialylated neoglycosphingolipids by using the polysialyltransferase from neuroinvasive Escherichia coli K1. Proc. Natl Acad. Sci. USA 91, 11427–11431 (1994).

    CAS  PubMed  Google Scholar 

  107. Michon, F., Brisson, J. R. & Jennings, H. J. Conformational differences between linear α(2–8)-linked homosialooligosaccharides and the epitope of the group B meningococcal polysaccharide. Biochemistry 26, 8399–8405 (1987).

    CAS  PubMed  Google Scholar 

  108. Maness, P. F. & Schachner, M. Neural recognition molecules of the immunoglobulin superfamily: signaling transducers of axon guidance and neuronal migration. Nature Neurosci. 10, 19–26 (2007).

    CAS  PubMed  Google Scholar 

  109. Polo-Parada, L., Plattner, F., Bose, C. & Landmesser, L. T. NCAM 180 acting via a conserved C-terminal domain and MLCK is essential for effective transmission with repetitive stimulation. Neuron 46, 917–931 (2005).

    CAS  Google Scholar 

  110. Kiselyov, V. V., Soroka, V., Berezin, V. & Bock, E. Structural biology of NCAM homophilic binding and activation of FGFR. J. Neurochem. 94, 1169–1179 (2005).

    CAS  PubMed  Google Scholar 

  111. Storms, S. D. & Rutishauser, U. A role for polysialic acid in neural cell adhesion molecule heterophilic binding to proteoglycans. J. Biol. Chem. 273, 27124–27129 (1998).

    CAS  PubMed  Google Scholar 

  112. Lackie, P. M., Zuber, C. & Roth, J. Polysialic acid of the neural cell adhesion molecule (N-CAM) is widely expressed during organogenesis in mesodermal and endodermal derivatives. Differentiation 57, 119–131 (1994).

    CAS  PubMed  Google Scholar 

  113. Moebius, J. M., Widera, D., Schmitz, J., Kaltschmidt, C. & Piechaczek, C. Impact of polysialylated CD56 on natural killer cell cytotoxicity. BMC Immunol. 8, 13 (2007).

    PubMed  PubMed Central  Google Scholar 

  114. Jimbo, T., Nakayama, J., Akahane, K. & Fukuda, M. Effect of polysialic acid on the tumor xenografts implanted into nude mice. Int. J. Cancer 94, 192–199 (2001).

    CAS  PubMed  Google Scholar 

  115. Suzuki, M. et al. Polysialic acid facilitates tumor invasion by glioma cells. Glycobiology 15, 887–894 (2005).

    CAS  PubMed  Google Scholar 

  116. Tomasiewicz, H. et al. Genetic deletion of a neural cell adhesion molecule variant (N-CAM-180) produces distinct defects in the central nervous system. Neuron 11, 1163–1174 (1993).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cell Biology, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, New York, 10021, New York, USA

    Urs Rutishauser

Authors
  1. Urs Rutishauser
    View author publications

    You can also search for this author in PubMed Google Scholar

Glossary

Plasticity

In neuroscience this is a broad term that refers to the ability of a cell or tissue to undergo biochemical, structural or physiological change. In different circumstances PSA can affect many types of plasticity in both the developing and adult nervous system.

Hydrated volume

The steric space that is occupied by a hydrophilic substance. Gels are examples of highly hydrated structures.

Steric repulsion

The force that is generated when two structures physically collide — in this case, proteins on apposing cell membranes. The force is enhanced by the presence of polysialic acid, due to its large hydrated volume.

Polysialyltransferase

A Golgi enzyme that adds sialic-acid residues to two specific asparagine-linked carbohydrate cores in NCAM to form very long linear polymers (comprising 50–300 residues).

Permissive regulation

Regulation that facilitates a process without directly altering the process itself, for example, PSA is permissive but not instructive for cell migration and axon outgrowth.

Insulative regulation

A regulatory mechanism by which the cell-surface coating provided by PSA allows a cell to ignore interactions with its environment.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rutishauser, U. Polysialic acid in the plasticity of the developing and adult vertebrate nervous system. Nat Rev Neurosci 9, 26–35 (2008). https://doi.org/10.1038/nrn2285

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn2285

This article is cited by

Search

Advanced 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