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:

Can regenerating axons recapitulate developmental guidance during recovery from spinal cord injury?

Key Points

  • Adult mammalian CNS regeneration is limited by a combination of intrinsic and extrinsic inhibitory barriers. This differs from the extraordinary ability to form short- and long-distance connections and complex circuits during nervous system development.

  • Various signalling molecules guide developing neuronal branches. Many of these molecules persist in adults, but in different quantitative and qualitative distributions.

  • The immature nervous system is refined by experience-dependent plasticity, resulting in the pruning of unnecessary connections and strengthening of useful ones. Mechanisms responsible for consolidating these refinements largely prevent further plastic changes, and secondarily inhibit regenerative responses in the context of injury.

  • Local network circuits termed central pattern generators (CPGs) regulate semi-automatic behaviours such as ambulation. CPG plasticity and adaptation depend on sensory feedback and voluntary input.

  • Intrinsic barriers to CNS regeneration include an unfavourable intracellular second messenger milieu as well as the inability to use regeneration-associated genes.

  • Extrinsic barriers to CNS regeneration include inhibitory molecules produced by oligodendrocytes, astrocytes and inflammatory cells. The altered distribution of growth and guidance factors in the adult relative to the developing nervous systems represents another extrinsic barrier to effective regeneration.

  • Advances using stem cells, neurotrophins and antagonists of extracellular inhibitors have resulted in a limited degree of CNS regeneration so far. Better approaches are required to recapitulate the precision of developmental growth, guidance and plasticity mechanisms.

  • One strategy to mimic the developmental milieu requires better understanding of the changes in distribution of key guidance molecules during and after development.

  • Rehabilitation approaches that maximize sensory feedback to CPGs will optimize the adaptation to loss of descending voluntary input.

Abstract

The precise wiring of the adult mammalian CNS originates during a period of stunning growth, guidance and plasticity that occurs during and shortly after development. When injured in adults, this intricate system fails to regenerate. Even when the obstacles to regeneration are cleared, growing adult CNS fibres usually remain misdirected and fail to reform functional connections. Here, we attempt to fill an important niche related to the topics of nervous system development and regeneration. We specifically contrast the difficulties faced by growing fibres within the adult context to the precise circuit-forming capabilities of developing fibres. In addition to focusing on methods to stimulate growth in the adult, we also expand on approaches to recapitulate development itself.

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: Corticospinal tract development.
Figure 2: Corticospinal tract response to injury.
Figure 3: Modes of circuit regeneration and plasticity after axotomy.

Similar content being viewed by others

References

  1. Hemmati-Brivanlou, A., Kelly, O. G. & Melton, D. A. Follistatin, an antagonist of activin, is expressed in the Spemann organizer and displays direct neuralizing activity. Cell 77, 283–295 (1994).

    CAS  PubMed  Google Scholar 

  2. Lamb, T. M. et al. Neural induction by the secreted polypeptide noggin. Science 262, 713–718 (1993).

    CAS  PubMed  Google Scholar 

  3. Lamb, T. M. & Harland, R. M. Fibroblast growth factor is a direct neural inducer, which combined with noggin generates anterior-posterior neural pattern. Development 121, 3627–3636 (1995).

    CAS  PubMed  Google Scholar 

  4. Durston, A. J. et al. Retinoic acid causes an anteroposterior transformation in the developing central nervous system. Nature 340, 140–144 (1989).

    CAS  PubMed  Google Scholar 

  5. Tanabe, Y. & Jessell, T. M. Diversity and pattern in the developing spinal cord. Science 274, 1115–1123 (1996).

    CAS  PubMed  Google Scholar 

  6. Muroyama, Y., Fujihara, M., Ikeya, M., Kondoh, H. & Takada, S. Wnt signaling plays an essential role in neuronal specification of the dorsal spinal cord. Genes Dev. 16, 548–553 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Yamada, T., Pfaff, S. L., Edlund, T. & Jessell, T. M. Control of cell pattern in the neural tube: motor neuron induction by diffusible factors from notochord and floor plate. Cell 73, 673–686 (1993).

    CAS  PubMed  Google Scholar 

  8. Echelard, Y. et al. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75, 1417–1430 (1993).

    CAS  PubMed  Google Scholar 

  9. Charron, F. & Tessier-Lavigne, M. Novel brain wiring functions for classical morphogens: a role as graded positional cues in axon guidance. Development 132, 2251–2262 (2005).

    CAS  PubMed  Google Scholar 

  10. Liu, Y. et al. Ryk-mediated Wnt repulsion regulates posterior-directed growth of corticospinal tract. Nature Neurosci. 8, 1151–1159 (2005). A convincing demonstration of gradient-guided CST development and the increasingly recognized multipurpose role of morphogens.

    CAS  PubMed  Google Scholar 

  11. Charron, F., Stein, E., Jeong, J., McMahon, A. P. & Tessier-Lavigne, M. The morphogen sonic hedgehog is an axonal chemoattractant that collaborates with netrin-1 in midline axon guidance. Cell 113, 11–23 (2003).

    CAS  PubMed  Google Scholar 

  12. Bourikas, D. et al. Sonic hedgehog guides commissural axons along the longitudinal axis of the spinal cord. Nature Neurosci. 8, 297–304 (2005).

    CAS  PubMed  Google Scholar 

  13. Lie, D. C. et al. Wnt signalling regulates adult hippocampal neurogenesis. Nature 437, 1370–1375 (2005).

    CAS  PubMed  Google Scholar 

  14. Lai, K., Kaspar, B. K., Gage, F. H. & Schaffer, D. V. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nature Neurosci. 6, 21–27 (2003).

    CAS  PubMed  Google Scholar 

  15. Chen, J., Magavi, S. S. & Macklis, J. D. Neurogenesis of corticospinal motor neurons extending spinal projections in adult mice. Proc. Natl Acad. Sci. USA 101, 16357–16362 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Doetsch, F., Caille, I., Lim, D. A., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97, 703–716 (1999).

    CAS  PubMed  Google Scholar 

  17. Horner, P. J. et al. Proliferation and differentiation of progenitor cells throughout the intact adult rat spinal cord. J. Neurosci. 20, 2218–2228 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Kempermann, G. & Gage, F. H. Neurogenesis in the adult hippocampus. Novartis Found. Symp. 231, 220–235; discussion 235–241, 302–306 (2000).

    CAS  PubMed  Google Scholar 

  19. Leavitt, B. R., Hernit-Grant, C. S. & Macklis, J. D. Mature astrocytes transform into transitional radial glia within adult mouse neocortex that supports directed migration of transplanted immature neurons. Exp. Neurol. 157, 43–57 (1999).

    CAS  PubMed  Google Scholar 

  20. Sotelo, C., Alvarado-Mallart, R. M., Frain, M. & Vernet, M. Molecular plasticity of adult Bergmann fibers is associated with radial migration of grafted Purkinje cells. J. Neurosci. 14, 124–133 (1994). Together with reference 19, this suggests that adult differentiated CNS glia retain the ability to revert to the radial glia phenotype to guide endogenous or exogenous immature migrating neurons.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  22. Koeberle, P. D. & Bahr, M. Growth and guidance cues for regenerating axons: where have they gone? J. Neurobiol. 59, 162–180 (2004).

    CAS  PubMed  Google Scholar 

  23. Serafini, T. et al. The netrins define a family of axon outgrowth-promoting proteins homologous to C. elegans UNC-6. Cell 78, 409–424 (1994).

    CAS  PubMed  Google Scholar 

  24. Kennedy, T. E., Serafini, T., de la Torre, J. R. & Tessier-Lavigne, M. Netrins are diffusible chemotropic factors for commissural axons in the embryonic spinal cord. Cell 78, 425–435 (1994).

    CAS  PubMed  Google Scholar 

  25. Harris, R., Sabatelli, L. M. & Seeger, M. A. Guidance cues at the Drosophila CNS midline: identification and characterization of two Drosophila Netrin/UNC-6 homologs. Neuron 17, 217–228 (1996).

    CAS  PubMed  Google Scholar 

  26. Brose, K. et al. Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance. Cell 96, 795–806 (1999).

    CAS  PubMed  Google Scholar 

  27. Kidd, T., Bland, K. S. & Goodman, C. S. Slit is the midline repellent for the robo receptor in Drosophila. Cell 96, 785–94 (1999).

    CAS  PubMed  Google Scholar 

  28. Li, H. S. et al. Vertebrate slit, a secreted ligand for the transmembrane protein roundabout, is a repellent for olfactory bulb axons. Cell 96, 807–818 (1999).

    CAS  PubMed  Google Scholar 

  29. Wang, K. H. et al. Biochemical purification of a mammalian slit protein as a positive regulator of sensory axon elongation and branching. Cell 96, 771–784 (1999).

    CAS  PubMed  Google Scholar 

  30. Sabatier, C. et al. The divergent Robo family protein rig-1/Robo3 is a negative regulator of slit responsiveness required for midline crossing by commissural axons. Cell 117, 157–169 (2004). Shows that, unlike isoforms 1 and 2, ROBO3 facilitates midline attraction rather than repulsion. In fact, ROBO3 is required for midline axon attraction, as its mutation in humans leads to the disorder HGPPS, in which multiple CNS tracts fail to cross the midline (see reference 60).

    CAS  PubMed  Google Scholar 

  31. Stein, E. & Tessier-Lavigne, M. Hierarchical organization of guidance receptors: silencing of netrin attraction by slit through a Robo/DCC receptor complex. Science 291, 1928–1938 (2001).

    CAS  PubMed  Google Scholar 

  32. Tessier-Lavigne, M. & Goodman, C. S. The molecular biology of axon guidance. Science 274, 1123–1133 (1996).

    CAS  PubMed  Google Scholar 

  33. Klein, R. Eph/ephrin signaling in morphogenesis, neural development and plasticity. Curr. Opin. Cell Biol. 16, 580–589 (2004).

    CAS  PubMed  Google Scholar 

  34. Martinez, A. & Soriano, E. Functions of ephrin/Eph interactions in the development of the nervous system: emphasis on the hippocampal system. Brain Res. Brain Res. Rev. 49, 211–226 (2005).

    CAS  PubMed  Google Scholar 

  35. Brown, A. et al. Topographic mapping from the retina to the midbrain is controlled by relative but not absolute levels of EphA receptor signaling. Cell 102, 77–88 (2000).

    CAS  PubMed  Google Scholar 

  36. Feldheim, D. A. et al. Genetic analysis of ephrin-A2 and ephrin-A5 shows their requirement in multiple aspects of retinocollicular mapping. Neuron 25, 563–574 (2000).

    CAS  PubMed  Google Scholar 

  37. Monnier, P. P. et al. RGM is a repulsive guidance molecule for retinal axons. Nature 419, 392–395 (2002).

    CAS  PubMed  Google Scholar 

  38. Rajagopalan, S. et al. Neogenin mediates the action of repulsive guidance molecule. Nature Cell Biol. 6, 756–762 (2004).

    CAS  PubMed  Google Scholar 

  39. Benson, M. D. et al. Ephrin-B3 is a myelin-based inhibitor of neurite outgrowth. Proc. Natl Acad. Sci. USA 102, 10694–10699 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Hata, K. et al. RGMa inhibition promotes axonal growth and recovery after spinal cord injury. J. Cell Biol. 173, 47–58 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Bach, H., Feldheim, D. A., Flanagan, J. G. & Scalia, F. Persistence of graded EphA/Ephrin-A expression in the adult frog visual system. J. Comp. Neurol. 467, 549–565 (2003).

    CAS  PubMed  Google Scholar 

  42. Liu, B. P. & Strittmatter, S. M. Semaphorin-mediated axonal guidance via Rho-related G proteins. Curr. Opin. Cell Biol. 13, 619–626 (2001).

    CAS  PubMed  Google Scholar 

  43. Kolodkin, A. L., Matthes, D. J. & Goodman, C. S. The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules. Cell 75, 1389–1399 (1993).

    CAS  PubMed  Google Scholar 

  44. Pasterkamp, R. J., Peschon, J. J., Spriggs, M. K. & Kolodkin, A. L. Semaphorin 7A promotes axon outgrowth through integrins and MAPKs. Nature 424, 398–405 (2003).

    PubMed  Google Scholar 

  45. Leonardo, E. D. et al. Vertebrate homologues of C. elegans UNC-5 are candidate netrin receptors. Nature 386, 833–838 (1997).

    CAS  PubMed  Google Scholar 

  46. Shewan, D., Dwivedy, A., Anderson, R. & Holt, C. E. Age-related changes underlie switch in netrin-1 responsiveness as growth cones advance along visual pathway. Nature Neurosci. 5, 955–962 (2002).

    CAS  PubMed  Google Scholar 

  47. Song, H. et al. Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides. Science 281, 1515–1518 (1998).

    CAS  PubMed  Google Scholar 

  48. Song, H. J. & Poo, M. M. Signal transduction underlying growth cone guidance by diffusible factors. Curr. Opin. Neurobiol. 9, 355–363 (1999).

    CAS  PubMed  Google Scholar 

  49. Chen, D. F., Jhaveri, S. & Schneider, G. E. Intrinsic changes in developing retinal neurons result in regenerative failure of their axons. Proc. Natl Acad. Sci. USA 92, 7287–7291 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Fawcett, J. W. Astrocytic and neuronal factors affecting axon regeneration in the damaged central nervous system. Cell Tissue Res. 290, 371–377 (1997).

    CAS  PubMed  Google Scholar 

  51. Cai, D. et al. Neuronal cyclic AMP controls the developmental loss in ability of axons to regenerate. J. Neurosci. 21, 4731–4739 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Dottori, M. et al. EphA4 (Sek1) receptor tyrosine kinase is required for the development of the corticospinal tract. Proc. Natl Acad. Sci. USA 95, 13248–13253 (1998). One of the first publications to link CST development to specific guidance molecules. Also describes the 'kangaroo-like' gait displayed by mice with various mutations affecting CST development.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Finger, J. H. et al. The netrin 1 receptors Unc5h3 and Dcc are necessary at multiple choice points for the guidance of corticospinal tract axons. J. Neurosci. 22, 10346–10356 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Kullander, K. et al. Ephrin-B3 is the midline barrier that prevents corticospinal tract axons from recrossing, allowing for unilateral motor control. Genes Dev. 15, 877–888 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  56. Kullander, K. et al. Role of EphA4 and EphrinB3 in local neuronal circuits that control walking. Science 299, 1889–1892 (2003). Previous papers (references 52 and 54) hinted that EphA4 or ephrin B3 knockout lead to a 'kangaroo-like' gait due to inappropriate CST midline crossing. Surprisingly, this paper demonstrates that the phenotype of these mice actually stems from aberrant crossing of segmental local interneurons within the CPG, rather than from defective CST development.

    CAS  PubMed  Google Scholar 

  57. Cohen, N. R. et al. Errors in corticospinal axon guidance in mice lacking the neural cell adhesion molecule L1. Curr. Biol. 8, 26–33 (1998).

    CAS  PubMed  Google Scholar 

  58. Graf, W. D. et al. Diffusion-weighted magnetic resonance imaging in boys with neural cell adhesion molecule L1 mutations and congenital hydrocephalus. Ann. Neurol. 47, 113–117 (2000).

    CAS  PubMed  Google Scholar 

  59. Castellani, V., Chedotal, A., Schachner, M., Faivre-Sarrailh, C. & Rougon, G. Analysis of the L1-deficient mouse phenotype reveals cross-talk between Sema3A and L1 signaling pathways in axonal guidance. Neuron 27, 237–249 (2000).

    CAS  PubMed  Google Scholar 

  60. Jen, J. C. et al. Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science 304, 1509–1513 (2004). Demonstrates in a human disease population the requirement for ROBO3 to mediate midline attraction and crossing in multiple CNS tracts (see also reference 30).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Oppenheim, R. W. Cell death during development of the nervous system. Annu. Rev. Neurosci. 14, 453–501 (1991).

    CAS  PubMed  Google Scholar 

  62. Luo, L. & O'Leary, D. D. Axon retraction and degeneration in development and disease. Annu. Rev. Neurosci. 28, 127–156 (2005).

    CAS  PubMed  Google Scholar 

  63. Levi-Montalcini, R. & Levi, G. Les conséquences de la destruction d'un territoire d'innervation périphérique sur le développement des centres nerveux correspondants dans l'embryon de poulet. Arch. Biol. 53, 537–545 (1942).

    Google Scholar 

  64. Hamburger, V. The effects of wing bug extirpation in chick embryos on the development of the central nervous system. J. Exp. Zool. 68, 449–494 (1934).

    Google Scholar 

  65. Hamburger, V. Cell death in the development of the lateral motor column of the chick embryo. J. Comp. Neurol. 160, 535–546 (1975).

    CAS  PubMed  Google Scholar 

  66. Hollyday, M. & Hamburger, V. Reduction of the naturally occurring motor neuron loss by enlargement of the periphery. J. Comp. Neurol. 170, 311–320 (1976).

    CAS  PubMed  Google Scholar 

  67. Goldberg, J. L. How does an axon grow? Genes Dev. 17, 941–958 (2003).

    CAS  PubMed  Google Scholar 

  68. Mendell, L. M. & Arvanian, V. L. Diversity of neurotrophin action in the postnatal spinal cord. Brain Res. Brain Res. Rev. 40, 230–239 (2002).

    CAS  PubMed  Google Scholar 

  69. Snider, W. D., Elliott, J. L. & Yan, Q. Axotomy-induced neuronal death during development. J. Neurobiol. 23, 1231–1246 (1992).

    CAS  PubMed  Google Scholar 

  70. Anand, U. et al. The effect of neurotrophic factors on morphology, TRPV1 expression and capsaicin responses of cultured human DRG sensory neurons. Neurosci. Lett. 399, 51–56 (2006).

    CAS  PubMed  Google Scholar 

  71. Hensch, T. K. Critical period plasticity in local cortical circuits. Nature Rev. Neurosci. 6, 877–888 (2005).

    CAS  Google Scholar 

  72. Knudsen, E. I. Instructed learning in the auditory localization pathway of the barn owl. Nature 417, 322–328 (2002).

    CAS  PubMed  Google Scholar 

  73. Knudsen, E. I. Capacity for plasticity in the adult owl auditory system expanded by juvenile experience. Science 279, 1531–1533 (1998).

    CAS  PubMed  Google Scholar 

  74. Hubel, D. H., Wiesel, T. N. & LeVay, S. Functional architecture of area 17 in normal and monocularly deprived macaque monkeys. Cold Spring Harb. Symp. Quant. Biol. 40, 581–589 (1976).

    CAS  PubMed  Google Scholar 

  75. Shatz, C. J. & Stryker, M. P. Ocular dominance in layer IV of the cat's visual cortex and the effects of monocular deprivation. J. Physiol. 281, 267–283 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Antonini, A., Fagiolini, M. & Stryker, M. P. Anatomical correlates of functional plasticity in mouse visual cortex. J. Neurosci. 19, 4388–4406 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Hensch, T. K. et al. Local GABA circuit control of experience-dependent plasticity in developing visual cortex. Science 282, 1504–1508 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Fagiolini, M. & Hensch, T. K. Inhibitory threshold for critical-period activation in primary visual cortex. Nature 404, 183–186 (2000).

    CAS  PubMed  Google Scholar 

  79. Huang, Z. J. et al. BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex. Cell 98, 739–755 (1999).

    CAS  PubMed  Google Scholar 

  80. Fagiolini, M. et al. Specific GABAA circuits for visual cortical plasticity. Science 303, 1681–1683 (2004).

    CAS  PubMed  Google Scholar 

  81. Keller-Peck, C. R. et al. Asynchronous synapse elimination in neonatal motor units: studies using GFP transgenic mice. Neuron 31, 381–394 (2001).

    CAS  PubMed  Google Scholar 

  82. De Paola, V. et al. Cell type-specific structural plasticity of axonal branches and boutons in the adult neocortex. Neuron 49, 861–875 (2006).

    CAS  PubMed  Google Scholar 

  83. Holtmaat, A. J. et al. Transient and persistent dendritic spines in the neocortex in vivo. Neuron 45, 279–291 (2005).

    CAS  PubMed  Google Scholar 

  84. Lee, W. C. et al. Dynamic remodeling of dendritic arbors in GABAergic interneurons of adult visual cortex. PLoS Biol 4, e29 (2006).

    PubMed  Google Scholar 

  85. Duysens, J. & Van de Crommert, H. W. Neural control of locomotion; the central pattern generator from cats to humans. Gait Posture 7, 131–141 (1998).

    CAS  PubMed  Google Scholar 

  86. Dietz, V. Spinal cord pattern generators for locomotion. Clin. Neurophysiol. 114, 1379–1389 (2003).

    CAS  PubMed  Google Scholar 

  87. Edgerton, V. R., Tillakaratne, N. J., Bigbee, A. J., de Leon, R. D. & Roy, R. R. Plasticity of the spinal neural circuitry after injury. Annu. Rev. Neurosci. 27, 145–167 (2004).

    CAS  PubMed  Google Scholar 

  88. Suster, M. L. & Bate, M. Embryonic assembly of a central pattern generator without sensory input. Nature 416, 174–178 (2002).

    CAS  PubMed  Google Scholar 

  89. Pearson, K. G. Generating the walking gait: role of sensory feedback. Prog. Brain Res. 143, 123–129 (2004).

    PubMed  Google Scholar 

  90. Walton, K. D., Lieberman, D., Llinas, A., Begin, M. & Llinas, R. R. Identification of a critical period for motor development in neonatal rats. Neuroscience 51, 763–767 (1992).

    CAS  PubMed  Google Scholar 

  91. Durkovic, R. G. & Damianopoulos, E. N. Forward and backward classical conditioning of the flexion reflex in the spinal cat. J. Neurosci. 6, 2921–2925 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Edgerton, V. R. et al. Potential of adult mammalian lumbosacral spinal cord to execute and acquire improved locomotion in the absence of supraspinal input. J. Neurotrauma 9, S119–S128 (1992).

    PubMed  Google Scholar 

  93. de Leon, R. D., Hodgson, J. A., Roy, R. R. & Edgerton, V. R. Locomotor capacity attributable to step training versus spontaneous recovery after spinalization in adult cats. J. Neurophysiol. 79, 1329–1340 (1998). One of many publications from the Edgerton group emphasizing the improved plasticity of intrinsic spinal cord circuits that is achieved with sensorimotor feedback training.

    CAS  PubMed  Google Scholar 

  94. Kudo, N., Nishimaru, H. & Nakayama, K. Developmental changes in rhythmic spinal neuronal activity in the rat fetus. Prog. Brain Res. 143, 49–55 (2004).

    PubMed  Google Scholar 

  95. Allain, A. E., Meyrand, P. & Branchereau, P. Ontogenic changes of the spinal GABAergic cell population are controlled by the serotonin (5-HT) system: implication of 5-HT1 receptor family. J. Neurosci. 25, 8714–8724 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. McGee, A. W., Yang, Y., Fischer, Q. S., Daw, N. W. & Strittmatter, S. M. Experience-driven plasticity of visual cortex limited by myelin and Nogo receptor. Science 309, 2222–2226 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Pizzorusso, T. et al. Reactivation of ocular dominance plasticity in the adult visual cortex. Science 298, 1248–1251 (2002). Using both immunohistological and functional techniques, together with reference 96, the authors begin to elucidate the molecular mechanisms of ocular dominance plasticity, identifying the key roles of CSPGs and MAIs.

    CAS  PubMed  Google Scholar 

  98. Lander, C., Kind, P., Maleski, M. & Hockfield, S. A family of activity-dependent neuronal cell-surface chondroitin sulfate proteoglycans in cat visual cortex. J. Neurosci. 17, 1928–1939 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Ferretti, P., Zhang, F. & O'Neill, P. Changes in spinal cord regenerative ability through phylogenesis and development: lessons to be learnt. Dev. Dyn. 226, 245–256 (2003). An interesting review that goes into more depth on the cellular and molecular mechanisms underlying the starkly contrasting ability of lower versus higher vertebrates to regenerate the injured CNS.

    PubMed  Google Scholar 

  100. Benowitz, L. I., Leon, S., Tabibiazar, R., Jing, Y. & Irwin, N. in Axonal Regeneration in the Central Nervous System (eds Ingoglia, N. A. & Murray, M.) 45–66 (Marcel Dekker, New York, 2001).

    Google Scholar 

  101. Saunders, N. R. et al. Development of walking, swimming and neuronal connections after complete spinal cord transection in the neonatal opossum, Monodelphis domestica. J. Neurosci. 18, 339–355 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Tom, V. J., Steinmetz, M. P., Miller, J. H., Doller, C. M. & Silver, J. Studies on the development and behavior of the dystrophic growth cone, the hallmark of regeneration failure, in an in vitro model of the glial scar and after spinal cord injury. J. Neurosci. 24, 6531–6539 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Kerschensteiner, M., Schwab, M. E., Lichtman, J. W. & Misgeld, T. In vivo imaging of axonal degeneration and regeneration in the injured spinal cord. Nature Med. 11, 572–577 (2005). A beautiful application of in vivo two-photon imaging of the mammalian CNS response to axonal injury. Confirms some of Ramón y Cajal's ingenious insights into transected fibre degeneration and regeneration.

    CAS  PubMed  Google Scholar 

  104. Ramón y Cajal, S., DeFelipe, J. & Jones, E. G. Cajal's Degeneration and Regeneration of the Nervous System (Oxford Univ. Press, New York, 1991).

    Google Scholar 

  105. Fawcett, J. W., Housden, E., Smith-Thomas, L. & Meyer, R. L. The growth of axons in three-dimensional astrocyte cultures. Dev. Biol. 135, 449–458 (1989).

    CAS  PubMed  Google Scholar 

  106. Goldberg, J. L., Klassen, M. P., Hua, Y. & Barres, B. A. Amacrine-signaled loss of intrinsic axon growth ability by retinal ganglion cells. Science 296, 1860–1864 (2002).

    CAS  PubMed  Google Scholar 

  107. Qiu, J. et al. Spinal axon regeneration induced by elevation of cyclic AMP. Neuron 34, 895–903 (2002).

    CAS  PubMed  Google Scholar 

  108. Gao, Y. et al. Activated CREB is sufficient to overcome inhibitors in myelin and promote spinal axon regeneration in vivo. Neuron 44, 609–621 (2004).

    CAS  PubMed  Google Scholar 

  109. Neumann, S. & Woolf, C. J. Regeneration of dorsal column fibers into and beyond the lesion site following adult spinal cord injury. Neuron 23, 83–91 (1999).

    CAS  PubMed  Google Scholar 

  110. Bonilla, I. E., Tanabe, K. & Strittmatter, S. M. Small proline-rich repeat protein 1A is expressed by axotomized neurons and promotes axonal outgrowth. J. Neurosci. 22, 1303–1315 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Cai, D. et al. Arginase I and polyamines act downstream from cyclic AMP in overcoming inhibition of axonal growth MAG and myelin in vitro. Neuron 35, 711–719 (2002).

    CAS  PubMed  Google Scholar 

  112. Marklund, N. et al. Selective temporal and regional alterations of Nogo-A and small proline-rich repeat protein 1A (SPRR1A) but not Nogo-66 receptor (NgR) occur following traumatic brain injury in the rat. Exp. Neurol. 197, 70–83 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Schmitt, A. B. et al. GAP-43 (B-50) and C-Jun are up-regulated in axotomized neurons of Clarke's nucleus after spinal cord injury in the adult rat. Neurobiol. Dis. 6, 122–130 (1999).

    CAS  PubMed  Google Scholar 

  114. Skene, J. H. & Willard, M. Characteristics of growth-associated polypeptides in regenerating toad retinal ganglion cell axons. J. Neurosci. 1, 419–426 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Tanabe, K., Bonilla, I., Winkles, J. A. & Strittmatter, S. M. Fibroblast growth factor-inducible-14 is induced in axotomized neurons and promotes neurite outgrowth. J. Neurosci. 23, 9675–9686 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Raivich, G. et al. The AP-1 transcription factor c-Jun is required for efficient axonal regeneration. Neuron 43, 57–67 (2004).

    CAS  PubMed  Google Scholar 

  117. Fournier, A. E., GrandPre, T. & Strittmatter, S. M. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature 409, 341–346 (2001).

    CAS  PubMed  Google Scholar 

  118. Mingorance, A. et al. Regulation of Nogo and Nogo receptor during the development of the entorhino-hippocampal pathway and after adult hippocampal lesions. Mol. Cell. Neurosci. 26, 34–49 (2004).

    CAS  PubMed  Google Scholar 

  119. Manitt, C., Thompson, K. M. & Kennedy, T. E. Developmental shift in expression of netrin receptors in the rat spinal cord: predominance of UNC-5 homologues in adulthood. J. Neurosci. Res. 77, 690–700 (2004).

    CAS  PubMed  Google Scholar 

  120. Ellezam, B., Selles-Navarro, I., Manitt, C., Kennedy, T. E. & McKerracher, L. Expression of netrin-1 and its receptors DCC and UNC-5H2 after axotomy and during regeneration of adult rat retinal ganglion cells. Exp. Neurol. 168, 105–115 (2001).

    CAS  PubMed  Google Scholar 

  121. David, S. & Aguayo, A. J. Axonal elongation into peripheral nervous system 'bridges' after central nervous system injury in adult rats. Science 214, 931–933 (1981). One of a series of papers from Aguayo's group that revives work that was first performed by Tello and Ramón y Cajal, demonstrating that CNS axons can indeed regenerate if provided with a permissive environment.

    CAS  PubMed  Google Scholar 

  122. Schwab, M. E. & Thoenen, H. Dissociated neurons regenerate into sciatic but not optic nerve explants in culture irrespective of neurotrophic factors. J. Neurosci. 5, 2415–2423 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Berry, M. Post-injury myelin-breakdown products inhibit axonal growth: an hypothesis to explain the failure of axonal regeneration in the mammalian central nervous system. Bibl. Anat. 23, 1–11 (1982). Demonstrates that the stimulatory effect of peripheral nerve grafts on CNS regeneration does not depend on neurotrophic factors unique to the peripheral milieu, but more likely reflects the presence of inhibitory factors in the CNS environment.

    Google Scholar 

  124. Schwab, M. E. & Bartholdi, D. Degeneration and regeneration of axons in the lesioned spinal cord. Physiol. Rev. 76, 319–370 (1996).

    CAS  PubMed  Google Scholar 

  125. Domeniconi, M. et al. Myelin-associated glycoprotein interacts with the Nogo66 receptor to inhibit neurite outgrowth. Neuron 35, 283–290 (2002).

    CAS  PubMed  Google Scholar 

  126. Liu, B. P., Fournier, A., GrandPre, T. & Strittmatter, S. M. Myelin-associated glycoprotein as a functional ligand for the Nogo-66 receptor. Science 297, 1190–1193 (2002).

    CAS  PubMed  Google Scholar 

  127. Wang, K. C. et al. Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417, 941–944 (2002).

    CAS  PubMed  Google Scholar 

  128. Huber, A. B., Weinmann, O., Brosamle, C., Oertle, T. & Schwab, M. E. Patterns of Nogo mRNA and protein expression in the developing and adult rat and after CNS lesions. J. Neurosci. 22, 3553–3567 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Wang, X. et al. Localization of Nogo-A and Nogo-66 receptor proteins at sites of axon–myelin and synaptic contact. J. Neurosci. 22, 5505–5515 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Oertle, T. & Schwab, M. E. Nogo and its paRTNers. Trends Cell Biol. 13, 187–194 (2003).

    CAS  PubMed  Google Scholar 

  131. Yiu, G. & He, Z. Glial inhibition of CNS axon regeneration. Nature Rev. Neurosci. 7, 617–627 (2006).

    CAS  Google Scholar 

  132. Schwab, M. E. Repairing the injured spinal cord. Science 295, 1029–1031 (2002).

    CAS  PubMed  Google Scholar 

  133. Thuret, S., Moon, L. D. F. & Gage, F. H. Therapeutic interventions after spinal cord injury. Nature Rev. Neurosci. 7, 628–643 (2006).

    CAS  Google Scholar 

  134. Fricker-Gates, R. A., Shin, J. J., Tai, C. C., Catapano, L. A. & Macklis, J. D. Late-stage immature neocortical neurons reconstruct interhemispheric connections and form synaptic contacts with increased efficiency in adult mouse cortex undergoing targeted neurodegeneration. J. Neurosci. 22, 4045–4056 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Lepore, A. C. et al. Long-term fate of neural precursor cells following transplantation into developing and adult CNS. Neuroscience 139, 513–530 (2006).

    CAS  PubMed  Google Scholar 

  136. Bregman, B. S. et al. Transplants and neurotrophic factors increase regeneration and recovery of function after spinal cord injury. Prog. Brain Res. 137, 257–273 (2002).

    CAS  PubMed  Google Scholar 

  137. Cummings, B. J. et al. Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice. Proc. Natl Acad. Sci. USA 102, 14069–14074 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Sheen, V. L. & Macklis, J. D. Targeted neocortical cell death in adult mice guides migration and differentiation of transplanted embryonic neurons. J. Neurosci. 15, 8378–8392 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Bregman, B. S., McAtee, M., Dai, H. N. & Kuhn, P. L. Neurotrophic factors increase axonal growth after spinal cord injury and transplantation in the adult rat. Exp. Neurol. 148, 475–494 (1997).

    CAS  PubMed  Google Scholar 

  140. Rao, M. S., Hattiangady, B. & Shetty, A. K. Fetal hippocampal CA3 cell grafts enriched with FGF-2 and BDNF exhibit robust long-term survival and integration and suppress aberrant mossy fiber sprouting in the injured middle-aged hippocampus. Neurobiol. Dis. 21, 276–290 (2006).

    CAS  PubMed  Google Scholar 

  141. Dumesnil-Bousez, N. & Sotelo, C. Partial reconstruction of the adult Lurcher cerebellar circuitry by neural grafting. Neuroscience 55, 1–21 (1993).

    CAS  PubMed  Google Scholar 

  142. Nakatomi, H. et al. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 110, 429–441 (2002).

    CAS  PubMed  Google Scholar 

  143. Magavi, S. S., Leavitt, B. R. & Macklis, J. D. Induction of neurogenesis in the neocortex of adult mice. Nature 405, 951–955 (2000).

    CAS  PubMed  Google Scholar 

  144. Arvidsson, A., Collin, T., Kirik, D., Kokaia, Z. & Lindvall, O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nature Med. 8, 963–970 (2002).

    CAS  PubMed  Google Scholar 

  145. Scharff, C., Kirn, J. R., Grossman, M., Macklis, J. D. & Nottebohm, F. Targeted neuronal death affects neuronal replacement and vocal behavior in adult songbirds. Neuron 25, 481–492 (2000).

    CAS  PubMed  Google Scholar 

  146. Kempermann, G., van Praag, H. & Gage, F. H. Activity-dependent regulation of neuronal plasticity and self repair. Prog. Brain Res. 127, 35–48 (2000).

    CAS  PubMed  Google Scholar 

  147. Lu, P., Yang, H., Jones, L. L., Filbin, M. T. & Tuszynski, M. H. Combinatorial therapy with neurotrophins and cAMP promotes axonal regeneration beyond sites of spinal cord injury. J. Neurosci. 24, 6402–6409 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Harper, J. M. et al. Axonal growth of embryonic stem cell-derived motoneurons in vitro and in motoneuron-injured adult rats. Proc. Natl Acad. Sci. USA 101, 7123–7128 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Bomze, H. M., Bulsara, K. R., Iskandar, B. J., Caroni, P. & Skene, J. H. Spinal axon regeneration evoked by replacing two growth cone proteins in adult neurons. Nature Neurosci. 4, 38–43 (2001).

    CAS  PubMed  Google Scholar 

  150. Grill, R., Murai, K., Blesch, A., Gage, F. H. & Tuszynski, M. H. Cellular delivery of neurotrophin-3 promotes corticospinal axonal growth and partial functional recovery after spinal cord injury. J. Neurosci. 17, 5560–5572 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Jakeman, L. B., Wei, P., Guan, Z. & Stokes, B. T. Brain-derived neurotrophic factor stimulates hindlimb stepping and sprouting of cholinergic fibers after spinal cord injury. Exp. Neurol. 154, 170–184 (1998).

    CAS  PubMed  Google Scholar 

  152. Houweling, D. A. et al. Local application of collagen containing brain-derived neurotrophic factor decreases the loss of function after spinal cord injury in the adult rat. Neurosci. Lett. 251, 193–196 (1998).

    CAS  PubMed  Google Scholar 

  153. Novikova, L., Novikov, L. & Kellerth, J. O. Brain-derived neurotrophic factor reduces necrotic zone and supports neuronal survival after spinal cord hemisection in adult rats. Neurosci. Lett. 220, 203–206 (1996).

    CAS  PubMed  Google Scholar 

  154. Jean, I., Lavialle, C., Barthelaix-Pouplard, A. & Fressinaud, C. Neurotrophin-3 specifically increases mature oligodendrocyte population and enhances remyelination after chemical demyelination of adult rat CNS. Brain Res. 972, 110–118 (2003).

    CAS  PubMed  Google Scholar 

  155. Hendriks, W. T., Ruitenberg, M. J., Blits, B., Boer, G. J. & Verhaagen, J. Viral vector-mediated gene transfer of neurotrophins to promote regeneration of the injured spinal cord. Prog. Brain Res. 146, 451–476 (2004).

    CAS  PubMed  Google Scholar 

  156. Palmer, T. D., Markakis, E. A., Willhoite, A. R., Safar, F. & Gage, F. H. Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS. J. Neurosci. 19, 8487–8497 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Kim, J. E., Liu, B. P., Park, J. H. & Strittmatter, S. M. Nogo-66 receptor prevents raphespinal and rubrospinal axon regeneration and limits functional recovery from spinal cord injury. Neuron 44, 439–451 (2004).

    CAS  PubMed  Google Scholar 

  158. Zheng, B. et al. Genetic deletion of the Nogo receptor does not reduce neurite inhibition in vitro or promote corticospinal tract regeneration in vivo. Proc. Natl Acad. Sci. USA 102, 1205–1210 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Lee, J. K., Kim, J. E., Sivula, M. & Strittmatter, S. M. Nogo receptor antagonism promotes stroke recovery by enhancing axonal plasticity. J. Neurosci. 24, 6209–6217 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Li, S. et al. Blockade of Nogo-66, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein by soluble Nogo-66 receptor promotes axonal sprouting and recovery after spinal injury. J. Neurosci. 24, 10511–10520 (2004). Shows that blocking the receptor for three major MAIs enhances CST regeneration following SCI, but growth is limited and proceeds along ectopic pathways.

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Markus, T. M. et al. Recovery and brain reorganization after stroke in adult and aged rats. Ann. Neurol. 58, 950–953 (2005).

    PubMed  Google Scholar 

  162. Liebscher, T. et al. Nogo-A antibody improves regeneration and locomotion of spinal cord-injured rats. Ann. Neurol. 58, 706–719 (2005). Shows that the blockade of Nogo-A's unique amino-terminal domain also improves axon regeneration, again in a limited, non-fasciculated pattern.

    CAS  PubMed  Google Scholar 

  163. Raineteau, O. & Schwab, M. E. Plasticity of motor systems after incomplete spinal cord injury. Nature Rev. Neurosci. 2, 263–273 (2001).

    CAS  Google Scholar 

  164. Cao, Q. et al. Functional recovery in traumatic spinal cord injury after transplantation of multineurotrophin-expressing glial-restricted precursor cells. J. Neurosci. 25, 6947–6957 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Niederost, B., Oertle, T., Fritsche, J., McKinney, R. A. & Bandtlow, C. E. Nogo-A and myelin-associated glycoprotein mediate neurite growth inhibition by antagonistic regulation of RhoA and Rac1. J. Neurosci. 22, 10368–10376 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Monnier, P. P., Sierra, A., Schwab, J. M., Henke-Fahle, S. & Mueller, B. K. The Rho/ROCK pathway mediates neurite growth-inhibitory activity associated with the chondroitin sulfate proteoglycans of the CNS glial scar. Mol. Cell. Neurosci. 22, 319–330 (2003).

    CAS  PubMed  Google Scholar 

  167. Dergham, P. et al. Rho signaling pathway targeted to promote spinal cord repair. J. Neurosci. 22, 6570–6577 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Ellezam, B. et al. Inactivation of intracellular Rho to stimulate axon growth and regeneration. Prog. Brain Res. 137, 371–380 (2002).

    CAS  PubMed  Google Scholar 

  169. Bertrand, J., Winton, M. J., Rodriguez-Hernandez, N., Campenot, R. B. & McKerracher, L. Application of Rho antagonist to neuronal cell bodies promotes neurite growth in compartmented cultures and regeneration of retinal ganglion cell axons in the optic nerve of adult rats. J. Neurosci. 25, 1113–1121 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Fournier, A. E., Takizawa, B. T. & Strittmatter, S. M. Rho kinase inhibition enhances axonal regeneration in the injured CNS. J. Neurosci. 23, 1416–1423 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Jain, A., Brady-Kalnay, S. M. & Bellamkonda, R. V. Modulation of Rho GTPase activity alleviates chondroitin sulfate proteoglycan-dependent inhibition of neurite extension. J. Neurosci. Res. 77, 299–307 (2004).

    CAS  PubMed  Google Scholar 

  172. Cafferty, W. B. J. & Strittmatter, S. M. Nogo/NgR mediated plasticity after spinal cord injury. Soc. Neurosci. Abstr. 719.8 (2005).

  173. Bradbury, E. J. et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 416, 636–640 (2002).

    CAS  PubMed  Google Scholar 

  174. Li, Y., Field, P. M. & Raisman, G. Repair of adult rat corticospinal tract by transplants of olfactory ensheathing cells. Science 277, 2000–2002 (1997).

    CAS  PubMed  Google Scholar 

  175. Li, Y., Sauve, Y., Li, D., Lund, R. D. & Raisman, G. Transplanted olfactory ensheathing cells promote regeneration of cut adult rat optic nerve axons. J. Neurosci. 23, 7783–7788 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Mueller, B. K., Mack, H. & Teusch, N. Rho kinase, a promising drug target for neurological disorders. Nature Rev. Drug Discov. 4, 387–398 (2005).

    CAS  Google Scholar 

  177. Bareyre, F. M. et al. The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nature Neurosci. 7, 269–277 (2004). A comprehensive demonstration of adult CNS plasticity in the context of incomplete SCI. An atypical but functional circuit bridges the lesion.

    CAS  PubMed  Google Scholar 

  178. Barbeau, H. & Rossignol, S. Recovery of locomotion after chronic spinalization in the adult cat. Brain Res. 412, 84–95 (1987).

    CAS  PubMed  Google Scholar 

  179. Rossignol, S. et al. Determinants of locomotor recovery after spinal injury in the cat. Prog. Brain Res. 143, 163–172 (2004). An extremely informative review from one of the giants in the field. Discusses the remarkable adaptability of the feline spinal cord locomotor CPG, and the roles of sensory feedback and neurotransmitters.

    PubMed  Google Scholar 

  180. De Leon, R. D., Hodgson, J. A., Roy, R. R. & Edgerton, V. R. Full weight-bearing hindlimb standing following stand training in the adult spinal cat. J. Neurophysiol. 80, 83–91 (1998).

    CAS  PubMed  Google Scholar 

  181. Bouyer, L. J. & Rossignol, S. The contribution of cutaneous inputs to locomotion in the intact and the spinal cat. Ann. NY Acad. Sci. 860, 508–512 (1998).

    CAS  PubMed  Google Scholar 

  182. Fung, J. & Barbeau, H. Effects of conditioning cutaneomuscular stimulation on the soleus H-reflex in normal and spastic paretic subjects during walking and standing. J. Neurophysiol. 72, 2090–2104 (1994).

    CAS  PubMed  Google Scholar 

  183. Bouyer, L. J. & Rossignol, S. Contribution of cutaneous inputs from the hindpaw to the control of locomotion. II. Spinal cats. J. Neurophysiol. 90, 3640–3653 (2003).

    CAS  PubMed  Google Scholar 

  184. Dietz, V., Colombo, G., Jensen, L. & Baumgartner, L. Locomotor capacity of spinal cord in paraplegic patients. Ann. Neurol. 37, 574–582 (1995).

    CAS  PubMed  Google Scholar 

  185. Wernig, A., Muller, S., Nanassy, A. & Cagol, E. Laufband therapy based on 'rules of spinal locomotion' is effective in spinal cord injured persons. Eur. J. Neurosci. 7, 823–829 (1995).

    CAS  PubMed  Google Scholar 

  186. Dobkin, B. et al. Weight-supported treadmill vs over-ground training for walking after acute incomplete SCI. Neurology 66, 484–493 (2006).

    CAS  PubMed  Google Scholar 

  187. Wolpaw, J. R. Treadmill training after spinal cord injury: good but not better. Neurology 66, 466–467 (2006). So far, references 186 and 187 report the most comprehensive and well-controlled clinical trial of BWSTT for SCI. The 'negative' result probably reflects the unexpectedly good outcome of the control group, which itself might represent improved rehabilitative therapy in general. This trial emphasizes the improving outlook for SCI patients with incomplete injuries.

    PubMed  Google Scholar 

  188. Wirz, M., Colombo, G. & Dietz, V. Long term effects of locomotor training in spinal humans. J. Neurol. Neurosurg. Psychiatr. 71, 93–96 (2001).

    CAS  Google Scholar 

  189. Curt, A., Schwab, M. E. & Dietz, V. Providing the clinical basis for new interventional therapies: refined diagnosis and assessment of recovery after spinal cord injury. Spinal Cord 42, 1–6 (2004).

    CAS  PubMed  Google Scholar 

  190. McGee, A. W. & Strittmatter, S. M. The Nogo-66 receptor: focusing myelin inhibition of axon regeneration. Trends Neurosci. 26, 193–198 (2003).

    CAS  PubMed  Google Scholar 

  191. Grados-Munro, E. M. & Fournier, A. E. Myelin-associated inhibitors of axon regeneration. J. Neurosci. Res. 74, 479–485 (2003).

    CAS  PubMed  Google Scholar 

  192. Schwab, M. E. Nogo and axon regeneration. Curr. Opin. Neurobiol. 14, 118–124 (2004).

    CAS  PubMed  Google Scholar 

  193. McKerracher, L. et al. Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth. Neuron 13, 805–811 (1994).

    CAS  PubMed  Google Scholar 

  194. Mukhopadhyay, G., Doherty, P., Walsh, F. S., Crocker, P. R. & Filbin, M. T. A novel role for myelin-associated glycoprotein as an inhibitor of axonal regeneration. Neuron 13, 757–767 (1994).

    CAS  PubMed  Google Scholar 

  195. Bartsch, U. et al. Lack of evidence that myelin-associated glycoprotein is a major inhibitor of axonal regeneration in the CNS. Neuron 15, 1375–1381 (1995).

    CAS  PubMed  Google Scholar 

  196. Chen, M. S. et al. Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 403, 434–439 (2000).

    CAS  PubMed  Google Scholar 

  197. GrandPre, T., Nakamura, F., Vartanian, T. & Strittmatter, S. M. Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature 403, 439–444 (2000).

    CAS  PubMed  Google Scholar 

  198. Prinjha, R. et al. Inhibitor of neurite outgrowth in humans. Nature 403, 383–384 (2000).

    CAS  PubMed  Google Scholar 

  199. Kim, J. E., Li, S., GrandPre, T., Qiu, D. & Strittmatter, S. M. Axon regeneration in young adult mice lacking Nogo-A/B. Neuron 38, 187–199 (2003).

    CAS  PubMed  Google Scholar 

  200. Simonen, M. et al. Systemic deletion of the myelin-associated outgrowth inhibitor Nogo-A improves regenerative and plastic responses after spinal cord injury. Neuron 38, 201–211 (2003).

    CAS  PubMed  Google Scholar 

  201. Zheng, B. et al. Lack of enhanced spinal regeneration in Nogo-deficient mice. Neuron 38, 213–224 (2003).

    CAS  PubMed  Google Scholar 

  202. Shao, Z. et al. TAJ/TROY, an orphan TNF receptor family member, binds Nogo-66 receptor 1 and regulates axonal regeneration. Neuron 45, 353–359 (2005).

    CAS  PubMed  Google Scholar 

  203. Mi, S. et al. LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nature Neurosci. 7, 221–228 (2004).

    CAS  PubMed  Google Scholar 

  204. Wang, K. C., Kim, J. A., Sivasankaran, R., Segal, R. & He, Z. P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature 420, 74–78 (2002).

    CAS  PubMed  Google Scholar 

  205. Barton, W. A. et al. Structure and axon outgrowth inhibitor binding of the Nogo-66 receptor and related proteins. EMBO J. 22, 3291–3302 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Lauren, J., Airaksinen, M. S., Saarma, M. & Timmusk, T. Two novel mammalian Nogo receptor homologs differentially expressed in the central and peripheral nervous systems. Mol. Cell. Neurosci. 24, 581–594 (2003).

    CAS  PubMed  Google Scholar 

  207. Venkatesh, K. et al. The Nogo-66 receptor homolog NgR2 is a sialic acid-dependent receptor selective for myelin-associated glycoprotein. J. Neurosci. 25, 808–822 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. Livesey, F. J. & Hunt, S. P. Netrin and netrin receptor expression in the embryonic mammalian nervous system suggests roles in retinal, striatal, nigral, and cerebellar development. Mol. Cell. Neurosci. 8, 417–429 (1997).

    CAS  PubMed  Google Scholar 

  209. Wang, H., Copeland, N. G., Gilbert, D. J., Jenkins, N. A. & Tessier-Lavigne, M. Netrin-3, a mouse homolog of human NTN2L, is highly expressed in sensory ganglia and shows differential binding to netrin receptors. J. Neurosci. 19, 4938–4947 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Manitt, C. et al. Widespread expression of netrin-1 by neurons and oligodendrocytes in the adult mammalian spinal cord. J. Neurosci. 21, 3911–3922 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Wehrle, R., Camand, E., Chedotal, A., Sotelo, C. & Dusart, I. Expression of netrin-1, slit-1 and slit-3 but not of slit-2 after cerebellar and spinal cord lesions. Eur. J. Neurosci. 22, 2134–2144 (2005).

    PubMed  Google Scholar 

  212. Gad, J. M., Keeling, S. L., Wilks, A. F., Tan, S. S. & Cooper, H. M. The expression patterns of guidance receptors, DCC and Neogenin, are spatially and temporally distinct throughout mouse embryogenesis. Dev. Biol. 192, 258–273 (1997).

    CAS  PubMed  Google Scholar 

  213. Gad, J. M., Keeling, S. L., Shu, T., Richards, L. J. & Cooper, H. M. The spatial and temporal expression patterns of netrin receptors, DCC and neogenin, in the developing mouse retina. Exp. Eye Res. 70, 711–722 (2000).

    CAS  PubMed  Google Scholar 

  214. Keino-Masu, K. et al. Deleted in Colorectal Cancer (DCC) encodes a netrin receptor. Cell 87, 175–185 (1996).

    CAS  PubMed  Google Scholar 

  215. Engelkamp, D. Cloning of three mouse Unc5 genes and their expression patterns at mid-gestation. Mech. Dev. 118, 191–197 (2002).

    CAS  PubMed  Google Scholar 

  216. Zhang, J. H., Cerretti, D. P., Yu, T., Flanagan, J. G. & Zhou, R. Detection of ligands in regions anatomically connected to neurons expressing the Eph receptor Bsk: potential roles in neuron–target interaction. J. Neurosci. 16, 7182–7192 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. O'Leary, D. D. & McLaughlin, T. Mechanisms of retinotopic map development: Ephs, ephrins, and spontaneous correlated retinal activity. Prog. Brain Res. 147, 43–65 (2005).

    CAS  PubMed  Google Scholar 

  218. Rodger, J. et al. Eph/ephrin expression in the adult rat visual system following localized retinal lesions: localized and transneuronal up-regulation in the retina and superior colliculus. Eur. J. Neurosci. 22, 1840–1852 (2005).

    CAS  PubMed  Google Scholar 

  219. Liebl, D. J., Morris, C. J., Henkemeyer, M. & Parada, L. F. mRNA expression of ephrins and Eph receptor tyrosine kinases in the neonatal and adult mouse central nervous system. J. Neurosci. Res. 71, 7–22 (2003). A comprehensive comparison of ephrin/Eph expression in the neonatal versus adult mouse CNS.

    CAS  PubMed  Google Scholar 

  220. Mori, T., Wanaka, A., Taguchi, A., Matsumoto, K. & Tohyama, M. Differential expressions of the eph family of receptor tyrosine kinase genes (sek, elk, eck) in the developing nervous system of the mouse. Brain Res. Mol. Brain Res. 29, 325–335 (1995).

    CAS  PubMed  Google Scholar 

  221. Irizarry-Ramirez, M. et al. Upregulation of EphA3 receptor after spinal cord injury. J. Neurotrauma 22, 929–935 (2005).

    PubMed  Google Scholar 

  222. Martone, M. E., Holash, J. A., Bayardo, A., Pasquale, E. B. & Ellisman, M. H. Immunolocalization of the receptor tyrosine kinase EphA4 in the adult rat central nervous system. Brain Res. 771, 238–250 (1997).

    CAS  PubMed  Google Scholar 

  223. Moreno-Flores, M. T. & Wandosell, F. Up-regulation of Eph tyrosine kinase receptors after excitotoxic injury in adult hippocampus. Neuroscience 91, 193–201 (1999).

    CAS  PubMed  Google Scholar 

  224. Goldshmit, Y., Galea, M. P., Wise, G., Bartlett, P. F. & Turnley, A. M. Axonal regeneration and lack of astrocytic gliosis in EphA4-deficient mice. J. Neurosci. 24, 10064–10073 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  225. Fabes, J. et al. Accumulation of the inhibitory receptor EphA4 may prevent regeneration of corticospinal tract axons following lesion. Eur. J. Neurosci. 23, 1721–1730 (2006).

    PubMed  Google Scholar 

  226. Liu, X., Hawkes, E., Ishimaru, T., Tran, T. & Sretavan, D. W. EphB3: an endogenous mediator of adult axonal plasticity and regrowth after CNS injury. J. Neurosci. 26, 3087–3101 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  227. Zhou, R. The Eph family receptors and ligands. Pharmacol. Ther. 77, 151–181 (1998).

    CAS  PubMed  Google Scholar 

  228. Bundesen, L. Q., Scheel, T. A., Bregman, B. S. & Kromer, L. F. Ephrin-B2 and EphB2 regulation of astrocyte-meningeal fibroblast interactions in response to spinal cord lesions in adult rats. J. Neurosci. 23, 7789–7800 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Holmes, G. P. et al. Distinct but overlapping expression patterns of two vertebrate slit homologs implies functional roles in CNS development and organogenesis. Mech. Dev. 79, 57–72 (1998).

    CAS  PubMed  Google Scholar 

  230. Marillat, V. et al. Spatiotemporal expression patterns of slit and robo genes in the rat brain. J. Comp. Neurol. 442, 130–155 (2002). An extensively detailed anatomical survey.

    PubMed  Google Scholar 

  231. Sundaresan, V. et al. Dynamic expression patterns of Robo (Robo1 and Robo2) in the developing murine central nervous system. J. Comp. Neurol. 468, 467–481 (2004).

    CAS  PubMed  Google Scholar 

  232. Marillat, V. et al. The slit receptor Rig-1/Robo3 controls midline crossing by hindbrain precerebellar neurons and axons. Neuron 43, 69–79 (2004).

    CAS  PubMed  Google Scholar 

  233. Chedotal, A. et al. Semaphorins III and IV repel hippocampal axons via two distinct receptors. Development 125, 4313–4323 (1998).

    CAS  PubMed  Google Scholar 

  234. Kolodkin, A. L. et al. Neuropilin is a semaphorin III receptor. Cell 90, 753–762 (1997).

    CAS  PubMed  Google Scholar 

  235. Pasterkamp, R. J., Anderson, P. N. & Verhaagen, J. Peripheral nerve injury fails to induce growth of lesioned ascending dorsal column axons into spinal cord scar tissue expressing the axon repellent Semaphorin3A. Eur. J. Neurosci. 13, 457–471 (2001).

    CAS  PubMed  Google Scholar 

  236. Pasterkamp, R. J. et al. Expression of the gene encoding the chemorepellent semaphorin III is induced in the fibroblast component of neural scar tissue formed following injuries of adult but not neonatal CNS. Mol. Cell. Neurosci. 13, 143–166 (1999).

    CAS  PubMed  Google Scholar 

  237. Giger, R. J., Pasterkamp, R. J., Heijnen, S., Holtmaat, A. J. & Verhaagen, J. Anatomical distribution of the chemorepellent semaphorin III/collapsin-1 in the adult rat and human brain: predominant expression in structures of the olfactory-hippocampal pathway and the motor system. J. Neurosci. Res. 52, 27–42 (1998).

    CAS  PubMed  Google Scholar 

  238. De Winter, F. et al. Injury-induced class 3 semaphorin expression in the rat spinal cord. Exp. Neurol. 175, 61–75 (2002).

    CAS  PubMed  Google Scholar 

  239. Sahay, A. et al. Secreted semaphorins modulate synaptic transmission in the adult hippocampus. J. Neurosci. 25, 3613–3620 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  240. Kawakami, A., Kitsukawa, T., Takagi, S. & Fujisawa, H. Developmentally regulated expression of a cell surface protein, neuropilin, in the mouse nervous system. J. Neurobiol. 29, 1–17 (1996).

    CAS  PubMed  Google Scholar 

  241. Tamagnone, L. et al. Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell 99, 71–80 (1999).

    CAS  PubMed  Google Scholar 

  242. Moreau-Fauvarque, C. et al. The transmembrane semaphorin Sema4D/CD100, an inhibitor of axonal growth, is expressed on oligodendrocytes and upregulated after CNS lesion. J. Neurosci. 23, 9229–9239 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  243. Schmidtmer, J. & Engelkamp, D. Isolation and expression pattern of three mouse homologues of chick Rgm. Gene Expr. Patterns 4, 105–110 (2004).

    CAS  PubMed  Google Scholar 

  244. Oldekamp, J., Kramer, N., Alvarez-Bolado, G. & Skutella, T. Expression pattern of the repulsive guidance molecules RGM A, B and C during mouse development. Gene Expr. Patterns 4, 283–288 (2004).

    CAS  PubMed  Google Scholar 

  245. Keeling, S. L., Gad, J. M. & Cooper, H. M. Mouse Neogenin, a DCC-like molecule, has four splice variants and is expressed widely in the adult mouse and during embryogenesis. Oncogene 15, 691–700 (1997).

    CAS  PubMed  Google Scholar 

  246. Barth, M., Hirsch, H. V., Meinertzhagen, I. A. & Heisenberg, M. Experience-dependent developmental plasticity in the optic lobe of Drosophila melanogaster. J. Neurosci. 17, 1493–1504 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  247. Brenowitz, E. A. & Beecher, M. D. Song learning in birds: diversity and plasticity, opportunities and challenges. Trends Neurosci. 28, 127–132 (2005).

    CAS  PubMed  Google Scholar 

  248. Gordon, J. A. & Stryker, M. P. Experience-dependent plasticity of binocular responses in the primary visual cortex of the mouse. J. Neurosci. 16, 3274–3286 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  249. Issa, N. P., Trachtenberg, J. T., Chapman, B., Zahs, K. R. & Stryker, M. P. The critical period for ocular dominance plasticity in the ferret's visual cortex. J. Neurosci. 19, 6965–6978 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  250. Olson, C. R. & Freeman, R. D. Profile of the sensitive period for monocular deprivation in kittens. Exp. Brain Res. 39, 17–21 (1980).

    CAS  PubMed  Google Scholar 

  251. Banks, M. S., Aslin, R. N. & Letson, R. D. Sensitive period for the development of human binocular vision. Science 190, 675–677 (1975).

    CAS  PubMed  Google Scholar 

  252. Berardi, N., Pizzorusso, T. & Maffei, L. Critical periods during sensory development. Curr. Opin. Neurobiol. 10, 138–145 (2000).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank members of the Strittmatter laboratory for critical discussions, especially B. P. Liu, S. O. Budel, W. B. Cafferty, Y. S. Yang, A. W. McGee, J. H. Park and E. C. Gunther for their extensive comments on this manuscript. J. B. Carmel also provided very helpful suggestions. This work was supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS), from the Christopher Reeve Paralysis Foundation and from the Falk Medical Research Trust (S.M.S.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Stephen M. Strittmatter.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Related links

Related links

DATABASES

OMIM

HGPPS

Glossary

Morphogens

Diffusible proteins that are involved in signalling the differentiation of cells into specific tissues and organs during embryogenesis. More recently, they have also been shown to have roles in axon guidance.

Radial glia

Progenitor cell type that gives rise to immature neurons and other radial glia. Immature neurons then migrate along radial glial processes.

Extracellular matrix

(ECM). Connective tissue produced largely by fibroblasts and astrocytes that provides diverse inhibitory and growth-promoting signals to neurons and their extensions.

Experience-dependent plasticity

The reorganization of neural circuits in response to excitatory and inhibitory synaptic influences. Involved in learning and adaptation to varying external stimuli.

Critical periods

Discrete phases early in life during which neural circuits exhibit maximal experience-dependent plasticity.

Ocular dominance

Neurons in the visual cortex respond electrophysiologically to light stimuli from one eye to a greater extent than to stimuli from the other eye. A model system for studying plasticity.

Monocular deprivation

Experimental model in which one eye is sutured shut during the critical period for ocular dominance plasticity, preventing experience-dependent changes.

Central pattern generators

(CPGs). Local circuits involved in coordinating largely automatic motor behaviours such as ambulation and swimming. Modulated by sensory feedback and descending voluntary inputs.

Chondroitin sulphate proteoglycans

(CSPGs).Carbohydrate-rich extracellular molecules with inhibitory effects on neurite outgrowth. Produced predominantly by astrocytes.

Myelin-associated inhibitors

(MAIs). Surface proteins expressed by oligodendrocytes that prevent neurite outgrowth or regeneration.

Regeneration-associated genes

Genes that are upregulated following axonal injury (for example, Gap43, Sprr 1a, Fn14 and arginase I). Increased expression correlates with regeneration in peripheral but not central neurons.

Body-weight-supported treadmill training

(BWSTT). Physical therapy technique for SCI patient's using a harness to partially support the patients weight while therapists assist the patient's legs to ambulate on a moving treadmill.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Harel, N., Strittmatter, S. Can regenerating axons recapitulate developmental guidance during recovery from spinal cord injury?. Nat Rev Neurosci 7, 603–616 (2006). https://doi.org/10.1038/nrn1957

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn1957

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