Abstract
Spinal cord injury (SCI) affects millions of people worldwide and causes a significant physical, emotional, social and economic burden. The main clinical hallmark of SCI is the permanent loss of motor, sensory and autonomic function below the level of injury. In general, neurons of the central nervous system (CNS) are incapable of regeneration, whereas injury to the peripheral nervous system is followed by axonal regeneration and usually results in some degree of functional recovery. The weak neuron-intrinsic regeneration-associated gene (RAG) response upon injury is an important reason for the failure of neurons in the CNS to regenerate an axon. This response consists of the expression of many RAGs, including regeneration-associated transcription factors (TFs). Regeneration-associated TFs are potential key regulators of the RAG program. The function of some regeneration-associated TFs has been studied in transgenic and knock-out mice and by adeno-associated viral vector-mediated overexpression in injured neurons. Here, we review these studies and propose that AAV-mediated gene delivery of combinations of regeneration-associated TFs is a potential strategy to activate the RAG program in injured CNS neurons and achieve long-distance axon regeneration.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abe, N., & Cavalli, V. (2008). Nerve injury signaling. Current Opinion in Neurobiology, 18, 276–283.
Aigner, L., Arber, S., Kapfhammer, J. P., Laux, T., Schneider, C., Botteri, F., et al. (1995). Overexpression of the neural growth-associated protein GAP-43 induces nerve sprouting in the adult nervous system of transgenic mice. Cell, 83, 269–278.
Anderson, P. N., Campbell, G., Zhang, Y., & Lieberman, A. R. (1998). Cellular and molecular correlates of the regeneration of adult mammalian CNS axons into peripheral nerve grafts. Progress in Brain Research, 117, 211–232.
Anderson, P. N., & Lieberman, A. R. (1999). Intrinsic determinants of differential axonal regeneration by adult mammalian CNS neurons. In N. R. Saunders & K. M. Dziegielewska (Eds.), Degeneration and regeneration in the nervous system (pp. 53–75). Amsterdam: Harwood Academic Press.
Andrews, M. R., Czvitkovich, S., Dassie, E., Vogelaar, C. F., Faissner, A., Blits, B., et al. (2009). Alpha9 integrin promotes neurite outgrowth on tenascin-C and enhances sensory axon regeneration. Journal of Neuroscience, 29, 5546–5557.
Bareyre, F. M., Garzorz, N., Lang, C., Misgeld, T., Buning, H., & Kerschensteiner, M. (2011). In vivo imaging reveals a phase-specific role of STAT3 during central and peripheral nervous system axon regeneration. Proceedings of the National Academy of Sciences of the USA, 108, 6282–6287.
Barritt, A. W., Davies, M., Marchand, F., Hartley, R., Grist, J., Yip, P., et al. (2006). Chondroitinase ABC promotes sprouting of intact and injured spinal systems after spinal cord injury. Journal of Neuroscience, 26, 10856–10867.
Becker, D., Sadowsky, C. L., & McDonald, J. W. (2003). Restoring function after spinal cord injury. Neurologist, 9, 1–15.
Benowitz, L. I., Shashoua, V. E., & Yoon, M. G. (1981). Specific changes in rapidly transported proteins during regeneration of the goldfish optic nerve. Journal of Neuroscience, 1, 300–307.
Benson, M. D., Romero, M. I., Lush, M. E., Lu, Q. R., Henkemeyer, M., & Parada, L. F. (2005). Ephrin-B3 is a myelin-based inhibitor of neurite outgrowth. Proceedings of the National Academy of Sciences of the USA, 102, 10694–10699.
Ben-Yaakov, K., Dagan, S. Y., Segal-Ruder, Y., Shalem, O., Vuppalanchi, D., Willis, D. E., et al. (2012). Axonal transcription factors signal retrogradely in lesioned peripheral nerve. EMBO Journal, 31, 1350–1363.
Berry, M. (1982). Post-injury myelin-breakdown products inhibit axonal growth: An hypothesis to explain the failure of axonal regeneration in the mammalian central nervous system. Bibliotheca Anatomica, 23, 1–11.
Blackmore, M. G., Moore, D. L., Smith, R. P., Goldberg, J. L., Bixby, J. L., & Lemmon, V. P. (2010). High content screening of cortical neurons identifies novel regulators of axon growth. Molecular and Cellular Neuroscience, 44, 43–54.
Blackmore, M. G., Wang, Z., Lerch, J. K., Motti, D., Zhang, Y. P., Shields, C. B., et al. (2012). Kruppel-like Factor 7 engineered for transcriptional activation promotes axon regeneration in the adult corticospinal tract. Proceedings of the National Academy of Sciences, 109, 7517–7522.
Blits, B., Derks, S., Twisk, J., Ehlert, E., Prins, J., & Verhaagen, J. (2010). Adeno-associated viral vector (AAV)-mediated gene transfer in the red nucleus of the adult rat brain: Comparative analysis of the transduction properties of seven AAV serotypes and lentiviral vectors. Journal of Neuroscience Methods, 185, 257–263.
Boeshore, K. L., Schreiber, R. C., Vaccariello, S. A., Sachs, H. H., Salazar, R., Lee, J., et al. (2004). Novel changes in gene expression following axotomy of a sympathetic ganglion: A microarray analysis. Journal of Neurobiology, 59, 216–235.
Bomze, H. M., Bulsara, K. R., Iskandar, B. J., Caroni, P., & Skene, J. H. (2001). Spinal axon regeneration evoked by replacing two growth cone proteins in adult neurons. Nature Neuroscience, 4, 38–43.
Bonilla, I. E., Tanabe, K., & Strittmatter, S. M. (2002). Small proline-rich repeat protein 1A is expressed by axotomized neurons and promotes axonal outgrowth. Journal of Neuroscience, 22, 1303–1315.
Bracken, M. B. (2012). Steroids for acute spinal cord injury. Cochrane Database System Review, 1, CD001046.
Bradbury, E. J., Moon, L. D., Popat, R. J., King, V. R., Bennett, G. S., Patel, P. N., et al. (2002). Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature, 416, 636–640.
Broude, E., McAtee, M., Kelley, M. S., & Bregman, B. S. (1997). c-Jun expression in adult rat dorsal root ganglion neurons: Differential response after central or peripheral axotomy. Experimental Neurology, 148, 367–377.
Buffo, A., Holtmaat, A. J., Savio, T., Verbeek, J. S., Oberdick, J., Oestreicher, A. B., et al. (1997). Targeted overexpression of the neurite growth-associated protein B-50/GAP-43 in cerebellar Purkinje cells induces sprouting after axotomy but not axon regeneration into growth-permissive transplants. Journal of Neuroscience, 17, 8778–8791.
Burger, C., Gorbatyuk, O. S., Velardo, M. J., Peden, C. S., Williams, P., Zolotukhin, S., et al. (2004). Recombinant AAV viral vectors pseudotyped with viral capsids from serotypes 1, 2, and 5 display differential efficiency and cell tropism after delivery to different regions of the central nervous system. Molecular Therapy, 10, 302–317.
Cafferty, W. B., Yang, S. H., Duffy, P. J., Li, S., & Strittmatter, S. M. (2007). Functional axonal regeneration through astrocytic scar genetically modified to digest chondroitin sulfate proteoglycans. Journal of Neuroscience, 27, 2176–2185.
Caggiano, A. O., Zimber, M. P., Ganguly, A., Blight, A. R., & Gruskin, E. A. (2005). Chondroitinase ABCI improves locomotion and bladder function following contusion injury of the rat spinal cord. Journal of Neurotrauma, 22, 226–239.
Caroni, P., & Schwab, M. E. (1988a). Antibody against myelin-associated inhibitor of neurite growth neutralizes nonpermissive substrate properties of CNS white matter. Neuron, 1, 85–96.
Caroni, P., & Schwab, M. E. (1988b). Two membrane protein fractions from rat central myelin with inhibitory properties for neurite growth and fibroblast spreading. Journal of Cell Biology, 106, 1281–1288.
Chen, M. S., Huber, A. B., van der Haar, M. E., Frank, M., Schnell, L., Spillmann, A. A., et al. (2000). Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature, 403, 434–439.
Cho, Y., & Cavalli, V. (2012). HDAC5 is a novel injury-regulated tubulin deacetylase controlling axon regeneration. EMBO Journal, 31, 3063–3078.
Cho, Y., & Cavalli, V. (2014). HDAC signaling in neuronal development and axon regeneration. Current Opinion in Neurobiology, 27C, 118–126.
Cho, Y., Sloutsky, R., Naegle, K. M., & Cavalli, V. (2013). Injury-induced HDAC5 nuclear export is essential for axon regeneration. Cell, 155, 894–908.
Chong, M. S., Woolf, C. J., Turmaine, M., Emson, P. C., & Anderson, P. N. (1996). Intrinsic versus extrinsic factors in determining the regeneration of the central processes of rat dorsal root ganglion neurons: The influence of a peripheral nerve graft. The Journal of Comparative Neurology, 370, 97–104.
Christie, S. D., Comeau, B., Myers, T., Sadi, D., Purdy, M., & Mendez, I. (2008). Duration of lipid peroxidation after acute spinal cord injury in rats and the effect of methylprednisolone. Neurosurgical Focus, 25, E5.
Costigan, M., Befort, K., Karchewski, L., Griffin, R. S., D’Urso, D., Allchorne, A., et al. (2002). Replicate high-density rat genome oligonucleotide microarrays reveal hundreds of regulated genes in the dorsal root ganglion after peripheral nerve injury. BMC Neuroscience, 3, 16.
David, S., & Aguayo, A. J. (1981). Axonal elongation into peripheral nervous system “bridges” after central nervous system injury in adult rats. Science, 214, 931–933.
Davies, S. J., Goucher, D. R., Doller, C., & Silver, J. (1999). Robust regeneration of adult sensory axons in degenerating white matter of the adult rat spinal cord. Journal of Neuroscience, 19, 5810–5822.
de Heredia, L. L., & Magoulas, C. (2013). Lack of the transcription factor C/EBPdelta impairs the intrinsic capacity of peripheral neurons for regeneration. Experimental Neurology, 239, 148–157.
De Winter, F., Oudega, M., Lankhorst, A. J., Hamers, F. P., Blits, B., Ruitenberg, M. J., et al. (2002). Injury-induced class 3 semaphorin expression in the rat spinal cord. Experimental Neurology, 175, 61–75.
Deumens, R., Koopmans, G. C., & Joosten, E. A. (2005). Regeneration of descending axon tracts after spinal cord injury. Progress in Neurobiology, 77, 57–89.
Devivo, M. J. (2012). Epidemiology of traumatic spinal cord injury: Trends and future implications. Spinal Cord, 50, 365–372.
Dimar, J. R., Glassman, S. D., Raque, G. H., Zhang, Y. P., Shields, C. B. (1999). The influence of spinal canal narrowing and timing of decompression on neurologic recovery after spinal cord contusion in a rat model. Spine (Phila Pa 1976), 24, 1623–1633.
Di Giovanni, S., Faden, A. I., Yakovlev, A., Duke-Cohan, J. S., Finn, T., Thouin, M., et al. (2005). Neuronal plasticity after spinal cord injury: Identification of a gene cluster driving neurite outgrowth. The FASEB Journal, 19, 153–154.
Di Giovanni, S., Knights, C. D., Rao, M., Yakovlev, A., Beers, J., Catania, J., et al. (2006). The tumor suppressor protein p53 is required for neurite outgrowth and axon regeneration. EMBO Journal, 25, 4084–4096.
Dididze, M., Green, B. A., Dietrich, W. D., Vanni, S., Wang, M. Y., & Levi, A. D. (2013). Systemic hypothermia in acute cervical spinal cord injury: A case-controlled study. Spinal Cord, 51, 395–400.
Dietrich, W. D., Levi, A. D., Wang, M., & Green, B. A. (2011). Hypothermic treatment for acute spinal cord injury. Neurotherapeutics, 8, 229–239.
Dinc, C., Iplikcioglu, A. C., Atabey, C., Eroglu, A., Topuz, K., Ipcioglu, O., Demirel, D. (2013). Comparison of deferoxamine and methylprednisolone: Protective effect of pharmacological agents on lipid peroxidation in spinal cord injury in rats. Spine (Phila Pa 1976), 38, E1649–E1655.
Donsante, A., Miller, D. G., Li, Y., Vogler, C., Brunt, E. M., Russell, D. W., et al. (2007). AAV vector integration sites in mouse hepatocellular carcinoma. Science, 317, 477.
Duh, M. S., Shepard, M. J., Wilberger, J. E., & Bracken, M. B. (1994). The effectiveness of surgery on the treatment of acute spinal cord injury and its relation to pharmacological treatment. Neurosurgery, 35, 240–248.
Fabes, J., Anderson, P., Brennan, C., & Bolsover, S. (2007). Regeneration-enhancing effects of EphA4 blocking peptide following corticospinal tract injury in adult rat spinal cord. European Journal of Neuroscience, 26, 2496–2505.
Fawcett, J. W., Schwab, M. E., Montani, L., Brazda, N., & Muller, H. W. (2012). Defeating inhibition of regeneration by scar and myelin components. Handbook of Clinical Neurology, 109, 503–522.
Fehlings, M. G., Perrin, R. G. (2006). The timing of surgical intervention in the treatment of spinal cord injury: A systematic review of recent clinical evidence. Spine (Phila Pa 1976), 31, S28–S35.
Fehlings, M. G., & Sekhon, L. H. (2000). Cellular, ionic and biomolecular mechanisms of the injury process. In C. H. Tator & E. C. Benzel (Eds.), Contemporary management of spinal cord injury: From impact to rehabilitation (pp. 33–50). New York: American Association of Neurological Surgeons.
Fernandes, K. J., Fan, D. P., Tsui, B. J., Cassar, S. L., & Tetzlaff, W. (1999). Influence of the axotomy to cell body distance in rat rubrospinal and spinal motoneurons: Differential regulation of GAP-43, tubulins, and neurofilament-M. Journal of Comparative Neurology, 414, 495–510.
Finelli, M. J., Wong, J. K., & Zou, H. (2013). Epigenetic regulation of sensory axon regeneration after spinal cord injury. Journal of Neuroscience, 33, 19664–19676.
Fleming, J., Ginn, S. L., Weinberger, R. P., Trahair, T. N., Smythe, J. A., & Alexander, I. E. (2001). Adeno-associated virus and lentivirus vectors mediate efficient and sustained transduction of cultured mouse and human dorsal root ganglia sensory neurons. Human Gene Therapy, 12, 77–86.
Fouad, K., Pearse, D. D., Tetzlaff, W., & Vavrek, R. (2009). Transplantation and repair: Combined cell implantation and chondroitinase delivery prevents deterioration of bladder function in rats with complete spinal cord injury. Spinal Cord, 47, 727–732.
Fouad, K., Schnell, L., Bunge, M. B., Schwab, M. E., Liebscher, T., & Pearse, D. D. (2005). Combining Schwann cell bridges and olfactory-ensheathing glia grafts with chondroitinase promotes locomotor recovery after complete transection of the spinal cord. Journal of Neuroscience, 25, 1169–1178.
Freund, P., Schmidlin, E., Wannier, T., Bloch, J., Mir, A., Schwab, M. E., et al. (2006). Nogo-A-specific antibody treatment enhances sprouting and functional recovery after cervical lesion in adult primates. Nature Medicine, 12, 790–792.
Freund, P., Schmidlin, E., Wannier, T., Bloch, J., Mir, A., Schwab, M. E., et al. (2009). Anti-Nogo-A antibody treatment promotes recovery of manual dexterity after unilateral cervical lesion in adult primates–re-examination and extension of behavioral data. European Journal of Neuroscience, 29, 983–996.
Gao, Y., Deng, K., Hou, J., Bryson, J. B., Barco, A., Nikulina, E., et al. (2004). Activated CREB is sufficient to overcome inhibitors in myelin and promote spinal axon regeneration in vivo. Neuron, 44, 609–621.
Garcia-Alias, G., Barkhuysen, S., Buckle, M., & Fawcett, J. W. (2009). Chondroitinase ABC treatment opens a window of opportunity for task-specific rehabilitation. Nature Neuroscience, 12, 1145–1151.
Garcia-Alias, G., & Fawcett, J. W. (2012). Training and anti-CSPG combination therapy for spinal cord injury. Experimental Neurology, 235, 26–32.
Garcia-Alias, G., Lin, R., Akrimi, S. F., Story, D., Bradbury, E. J., & Fawcett, J. W. (2008). Therapeutic time window for the application of chondroitinase ABC after spinal cord injury. Experimental Neurology, 210, 331–338.
Gaub, P., Joshi, Y., Wuttke, A., Naumann, U., Schnichels, S., Heiduschka, P., et al. (2011). The histone acetyltransferase p300 promotes intrinsic axonal regeneration. Brain, 134, 2134–2148.
Giger, R. J., Hollis, E. R., & Tuszynski, M. H. (2010). Guidance molecules in axon regeneration. Cold Spring Harbor Perspectives in Biology, 2, a001867.
Glatzel, M., Flechsig, E., Navarro, B., Klein, M. A., Paterna, J. C., Bueler, H., et al. (2000). Adenoviral and adeno-associated viral transfer of genes to the peripheral nervous system. Proceedings of the National Academy of Sciences of the USA, 97, 442–447.
Goldberg, J. L., Klassen, M. P., Hua, Y., & Barres, B. A. (2002). Amacrine-signaled loss of intrinsic axon growth ability by retinal ganglion cells. Science, 296, 1860–1864.
Goldberg, J. L., Vargas, M. E., Wang, J. T., Mandemakers, W., Oster, S. F., Sretavan, D. W., et al. (2004). An oligodendrocyte lineage-specific semaphorin, Sema5A, inhibits axon growth by retinal ganglion cells. Journal of Neuroscience, 24, 4989–4999.
Goldshmit, Y., Galea, M. P., Wise, G., Bartlett, P. F., & Turnley, A. M. (2004). Axonal regeneration and lack of astrocytic gliosis in EphA4-deficient mice. Journal of Neuroscience, 24, 10064–10073.
Goldshmit, Y., Spanevello, M. D., Tajouri, S., Li, L., Rogers, F., Pearse, M., et al. (2011). EphA4 blockers promote axonal regeneration and functional recovery following spinal cord injury in mice. PLoS ONE, 6, e24636.
Gonzenbach, R. R., Zoerner, B., Schnell, L., Weinmann, O., Mir, A. K., & Schwab, M. E. (2012). Delayed anti-nogo-a antibody application after spinal cord injury shows progressive loss of responsiveness. Journal of Neurotrauma, 29, 567–578.
Goritz, C., Dias, D. O., Tomilin, N., Barbacid, M., Shupliakov, O., & Frisen, J. (2011). A pericyte origin of spinal cord scar tissue. Science, 333, 238–242.
GrandPre, T., Nakamura, F., Vartanian, T., & Strittmatter, S. M. (2000). Identification of the Nogo inhibitor of axon regeneration as a reticulon protein. Nature, 403, 439–444.
Gruener, G., Biller, J. (2008). Spinal cord anatomy, localization, and overview of spinal cord syndromes. Continuum: Lifelong Learning Neurology, 14, 11–35.
Hall, E. D., & Braughler, J. M. (1982a). Effects of intravenous methylprednisolone on spinal cord lipid peroxidation and Na + + K +)-ATPase activity. Dose-response analysis during 1st hour after contusion injury in the cat. Journal of Neurosurgery, 57, 247–253.
Hall, E. D., & Braughler, J. M. (1982b). Glucocorticoid mechanisms in acute spinal cord injury: A review and therapeutic rationale. Surgical Neurology, 18, 320–327.
Harrison, P. T., Dalziel, R. G., Ditchfield, N. A., & Quinn, J. P. (1999). Neuronal-specific and nerve growth factor-inducible expression directed by the preprotachykinin-A promoter delivered by an adeno-associated virus vector. Neuroscience, 94, 997–1003.
Harrop, J. S. (2014). Spinal cord injury: Debating the efficacy of methylprednisolone. Neurosurgery, 61(Suppl 1), 30–31.
Hellstrom, M., Muhling, J., Ehlert, E. M., Verhaagen, J., Pollett, M. A., Hu, Y., et al. (2011). Negative impact of rAAV2 mediated expression of SOCS3 on the regeneration of adult retinal ganglion cell axons. Molecular and Cellular Neuroscience, 46, 507–515.
Hermens, W. T., & Verhaagen, J. (1998). Viral vectors, tools for gene transfer in the nervous system. Progress in Neurobiology, 55, 399–432.
Holmes, F. E., Mahoney, S., King, V. R., Bacon, A., Kerr, N. C., Pachnis, V., et al. (2000). Targeted disruption of the galanin gene reduces the number of sensory neurons and their regenerative capacity. Proceedings of the National Academy of Sciences of the USA, 97, 11563–11568.
Holtmaat, A. J., Dijkhuizen, P. A., Oestreicher, A. B., Romijn, H. J., Van der Lugt, N. M., Berns, A., et al. (1995). Directed expression of the growth-associated protein B-50/GAP-43 to olfactory neurons in transgenic mice results in changes in axon morphology and extraglomerular fiber growth. Journal of Neuroscience, 15, 7953–7965.
Holtmaat, A. J., Hermens, W. T., Sonnemans, M. A., Giger, R. J., Van Leeuwen, F. W., Kaplitt, M. G., et al. (1997). Adenoviral vector-mediated expression of B-50/GAP-43 induces alterations in the membrane organization of olfactory axon terminals in vivo. Journal of Neuroscience, 17, 6575–6586.
Houle, J. D., Tom, V. J., Mayes, D., Wagoner, G., Phillips, N., & Silver, J. (2006). Combining an autologous peripheral nervous system “bridge” and matrix modification by chondroitinase allows robust, functional regeneration beyond a hemisection lesion of the adult rat spinal cord. Journal of Neuroscience, 26, 7405–7415.
Ikegami, T., Nakamura, M., Yamane, J., Katoh, H., Okada, S., Iwanami, A., et al. (2005). Chondroitinase ABC combined with neural stem/progenitor cell transplantation enhances graft cell migration and outgrowth of growth-associated protein-43-positive fibers after rat spinal cord injury. European Journal of Neuroscience, 22, 3036–3046.
Jankowski, M. P., Cornuet, P. K., McIlwrath, S., Koerber, H. R., & Albers, K. M. (2006). SRY-box containing gene 11 (Sox11) transcription factor is required for neuron survival and neurite growth. Neuroscience, 143, 501–514.
Jankowski, M. P., McIlwrath, S. L., Jing, X., Cornuet, P. K., Salerno, K. M., Koerber, H. R., et al. (2009). Sox11 transcription factor modulates peripheral nerve regeneration in adult mice. Brain Research, 1256, 43–54.
Jing, X., Wang, T., Huang, S., Glorioso, J. C., & Albers, K. M. (2012). The transcription factor Sox11 promotes nerve regeneration through activation of the regeneration-associated gene Sprr1a. Experimental neurology, 233, 221–232.
Kaeppel, C., Beattie, S. G., Fronza, R., van, L. R., Salmon, F., Schmidt, S., Wolf, S., Nowrouzi, A., Glimm, H., von, K. C., Petry, H., Gaudet, D., Schmidt, M. (2013). A largely random AAV integration profile after LPLD gene therapy. Nat Med, 19, 889–891.
Kajimura, D., Dragomir, C., Ramirez, F., & Laub, F. (2007). Identification of genes regulated by transcription factor KLF7 in differentiating olfactory sensory neurons. Gene, 388, 34–42.
Kaneko, S., Iwanami, A., Nakamura, M., Kishino, A., Kikuchi, K., Shibata, S., et al. (2006). A selective Sema3A inhibitor enhances regenerative responses and functional recovery of the injured spinal cord. Nature Medicine, 12, 1380–1389.
Kaplitt, M. G., Feigin, A., Tang, C., Fitzsimons, H. L., Mattis, P., Lawlor, P. A, Bland, R. J., Young, D., Strybing, K., Eidelberg, D., During, M. J. (2007). Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson’s disease: An open label, phase I trial. 2097–2105.
Kaplitt, M. G., Leone, P., Samulski, R. J., Xiao, X., Pfaff, D. W., O’Malley, K. L., et al. (1994). Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain. Nature Genetics, 8, 148–154.
Karimi-Abdolrezaee, S., Eftekharpour, E., Wang, J., Schut, D., & Fehlings, M. G. (2010). Synergistic effects of transplanted adult neural stem/progenitor cells, chondroitinase, and growth factors promote functional repair and plasticity of the chronically injured spinal cord. Journal of Neuroscience, 30, 1657–1676.
Karimi-Abdolrezaee, S., Schut, D., Wang, J., & Fehlings, M. G. (2012). Chondroitinase and growth factors enhance activation and oligodendrocyte differentiation of endogenous neural precursor cells after spinal cord injury. PLoS ONE, 7, e37589.
Kikuchi, K., Kishino, A., Konishi, O., Kumagai, K., Hosotani, N., Saji, I., et al. (2003). In vitro and in vivo characterization of a novel semaphorin 3A inhibitor, SM-216289 or xanthofulvin. Journal of Biological Chemistry, 278, 42985–42991.
Kingsbury, T. J., & Krueger, B. K. (2007). Ca2 + , CREB and kruppel: A novel KLF7-binding element conserved in mouse and human TRKB promoters is required for CREB-dependent transcription. Molecular and Cellular Neuroscience, 35, 447–455.
Kirik, D., & Bjorklund, A. (2003). Modeling CNS neurodegeneration by overexpression of disease-causing proteins using viral vectors. Trends in Neurosciences, 26, 386–392.
Klein, R. L., McNamara, R. K., King, M. A., Lenox, R. H., Muzyczka, N., & Meyer, E. M. (1999). Generation of aberrant sprouting in the adult rat brain by GAP-43 somatic gene transfer. Brain Research, 832, 136–144.
Koerber, J. T., Klimczak, R., Jang, J. H., Dalkara, D., Flannery, J. G., & Schaffer, D. V. (2009). Molecular evolution of adeno-associated virus for enhanced glial gene delivery. Molecular Therapy, 17, 2088–2095.
Komiya, Y. (1981). Axonal regeneration in bifurcating axons of rat dorsal root ganglion cells. Experimental Neurology, 73, 824–826.
Kwon, I., & Schaffer, D. V. (2008). Designer gene delivery vectors: Molecular engineering and evolution of adeno-associated viral vectors for enhanced gene transfer. Pharmaceutical Research, 25, 489–499.
Lang, C., Bradley, P. M., Jacobi, A., Kerschensteiner, M., & Bareyre, F. M. (2013). STAT3 promotes corticospinal remodelling and functional recovery after spinal cord injury. EMBO Reports, 14, 931–937.
Lee, J. K., Chow, R., Xie, F., Chow, S. Y., Tolentino, K. E., & Zheng, B. (2010a). Combined genetic attenuation of myelin and semaphorin-mediated growth inhibition is insufficient to promote serotonergic axon regeneration. Journal of Neuroscience, 30, 10899–10904.
Lee, J. K., Geoffroy, C. G., Chan, A. F., Tolentino, K. E., Crawford, M. J., Leal, M. A., et al. (2010b). Assessing spinal axon regeneration and sprouting in Nogo-, MAG-, and OMgp-deficient mice. Neuron, 66, 663–670.
Lei, L., Laub, F., Lush, M., Romero, M., Zhou, J., Luikart, B., et al. (2005). The zinc finger transcription factor Klf7 is required for TrkA gene expression and development of nociceptive sensory neurons. Genes & Development, 19, 1354–1364.
LeWitt, P. A., et al. (2011). AAV2-GAD gene therapy for advanced Parkinson’s disease: A double-blind, sham-surgery controlled, randomised trial. Lancet Neurology, 10, 309–319.
Liebscher, T., Schnell, L., Schnell, D., Scholl, J., Schneider, R., Gullo, M., et al. (2005). Nogo-A antibody improves regeneration and locomotion of spinal cord-injured rats. Ann Neurol, 58, 706–719.
Lindner, R., Puttagunta, R., & Di, G. S. (2013). Epigenetic regulation of axon outgrowth and regeneration in CNS injury: The first steps forward. Neurotherapeutics, 10, 771–781.
Liu, K., Lu, Y., Lee, J. K., Samara, R., Willenberg, R., Sears-Kraxberger, I., et al. (2010). PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nature Neuroscience, 13, 1075–1081.
Lorber, B., Howe, M. L., Benowitz, L. I., & Irwin, N. (2009). Mst3b, an Ste20-like kinase, regulates axon regeneration in mature CNS and PNS pathways. Nature Neuroscience, 12, 1407–1414.
Ma, W., & Bisby, M. A. (1998). Increased activation of nuclear factor kappa B in rat lumbar dorsal root ganglion neurons following partial sciatic nerve injuries. Brain Research, 797, 243–254.
Macgillavry, H. D., Cornelis, J., van der Kallen, L. R., Sassen, M. M., Verhaagen, J., Smit, A. B., et al. (2011). Genome-wide gene expression and promoter binding analysis identifies NFIL3 as a repressor of C/EBP target genes in neuronal outgrowth. Molecular and Cellular Neuroscience, 46, 460–468.
Macgillavry, H. D., Stam, F. J., Sassen, M. M., Kegel, L., Hendriks, W. T., Verhaagen, J., et al. (2009). NFIL3 and cAMP response element-binding protein form a transcriptional feed forward loop that controls neuronal regeneration-associated gene expression. Journal of Neuroscience, 29, 15542–15550.
Makwana, M., & Raivich, G. (2005). Molecular mechanisms in successful peripheral regeneration. FEBS Journal, 272, 2628–2638.
Mason, M. R., Campbell, G., Caroni, P., Anderson, P. N., & Lieberman, A. R. (2000). Overexpression of GAP-43 in thalamic projection neurons of transgenic mice does not enable them to regenerate axons through peripheral nerve grafts. Experimental Neurology, 165, 143–152.
Mason, M. R., Ehlert, E. M., Eggers, R., Pool, C. W., Hermening, S., Huseinovic, A., et al. (2010). Comparison of AAV serotypes for gene delivery to dorsal root ganglion neurons. Molecular Therapy, 18, 715–724.
Mason, M. R., Lieberman, A. R., & Anderson, P. N. (2003). Corticospinal neurons up-regulate a range of growth-associated genes following intracortical, but not spinal, axotomy. European Journal of Neuroscience, 18, 789–802.
Mason, M. R., Lieberman, A. R., Grenningloh, G., & Anderson, P. N. (2002). Transcriptional upregulation of SCG10 and CAP-23 is correlated with regeneration of the axons of peripheral and central neurons in vivo. Molecular and Cellular Neuroscience, 20, 595–615.
Mason, M. R., Tannemaat, M. R., Malessy, M. J., & Verhaagen, J. (2011). Gene therapy for the peripheral nervous system: A strategy to repair the injured nerve? Current Gene Therapy, 11, 75–89.
Massey, J. M., Amps, J., Viapiano, M. S., Matthews, R. T., Wagoner, M. R., Whitaker, C. M., et al. (2008). Increased chondroitin sulfate proteoglycan expression in denervated brainstem targets following spinal cord injury creates a barrier to axonal regeneration overcome by chondroitinase ABC and neurotrophin-3. Experimental Neurology, 209, 426–445.
Massey, J. M., Hubscher, C. H., Wagoner, M. R., Decker, J. A., Amps, J., Silver, J., et al. (2006). Chondroitinase ABC digestion of the perineuronal net promotes functional collateral sprouting in the cuneate nucleus after cervical spinal cord injury. Journal of Neuroscience, 26, 4406–4414.
McDonald, J. W., & Sadowsky, C. (2002). Spinal-cord injury. Lancet, 359, 417–425.
McFarland, N. R., Lee, J. S., Hyman, B. T., & McLean, P. J. (2009). Comparison of transduction efficiency of recombinant AAV serotypes 1, 2, 5, and 8 in the rat nigrostriatal system. Journal of Neurochemistry, 109, 838–845.
McKeon, R. J., Schreiber, R. C., Rudge, J. S., & Silver, J. (1991). Reduction of neurite outgrowth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes. Journal of Neuroscience, 11, 3398–3411.
McKerracher, L., David, S., Jackson, D. L., Kottis, V., Dunn, R. J., & Braun, P. E. (1994). Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth. Neuron, 13, 805–811.
Mechaly, I., Bourane, S., Piquemal, D., Al-Jumaily, M., Venteo, S., Puech, S., et al. (2006). Gene profiling during development and after a peripheral nerve traumatism reveals genes specifically induced by injury in dorsal root ganglia. Molecular and Cellular Neuroscience, 32, 217–229.
Michaelevski, I., Segal-Ruder, Y., Rozenbaum, M., Medzihradszky, K. F., Shalem, O., Coppola, G., Horn-Saban, S., Ben-Yaakov, K., Dagan, S. Y., Rishal, I., Geschwind, D. H., Pilpel, Y., Burlingame, A. L., Fainzilber, M. (2010). Signaling to transcription networks in the neuronal retrograde injury response. Science Signaling, 3, ra53.
Moon, L. D., Asher, R. A., Rhodes, K. E., & Fawcett, J. W. (2001). Regeneration of CNS axons back to their target following treatment of adult rat brain with chondroitinase ABC. Nature Neuroscience, 4, 465–466.
Moore, D. L., Blackmore, M. G., Hu, Y., Kaestner, K. H., Bixby, J. L., Lemmon, V. P., et al. (2009). KLF family members regulate intrinsic axon regeneration ability. Science, 326, 298–301.
Moore, D. L., & Goldberg, J. L. (2011). Multiple transcription factor families regulate axon growth and regeneration. Developmental Neurobiology, 71, 1186–1211.
Moreau-Fauvarque, C., Kumanogoh, A., Camand, E., Jaillard, C., Barbin, G., Boquet, I., et al. (2003). The transmembrane semaphorin Sema4D/CD100, an inhibitor of axonal growth, is expressed on oligodendrocytes and upregulated after CNS lesion. Journal of Neuroscience, 23, 9229–9239.
Mukhopadhyay, G., Doherty, P., Walsh, F. S., Crocker, P. R., & Filbin, M. T. (1994). A novel role for myelin-associated glycoprotein as an inhibitor of axonal regeneration. Neuron, 13, 757–767.
Nadeau, S., Hein, P., Fernandes, K. J., Peterson, A. C., & Miller, F. D. (2005). A transcriptional role for C/EBP beta in the neuronal response to axonal injury. Molecular and Cellular Neuroscience, 29, 525–535.
New, P. W., Rawicki, H. B., & Bailey, M. J. (2002). Nontraumatic spinal cord injury: Demographic characteristics and complications. Archives of Physical Medicine and Rehabilitation, 83, 996–1001.
Nguyen, T., Lindner, R., Tedeschi, A., Forsberg, K., Green, A., Wuttke, A., et al. (2009). NFAT-3 is a transcriptional repressor of the growth-associated protein 43 during neuronal maturation. Journal of Biological Chemistry, 284, 18816–18823.
Niederost, B. P., Zimmermann, D. R., Schwab, M. E., & Bandtlow, C. E. (1999). Bovine CNS myelin contains neurite growth-inhibitory activity associated with chondroitin sulfate proteoglycans. Journal of Neuroscience, 19, 8979–8989.
Nilsson, A., Moller, K., Dahlin, L., Lundborg, G., & Kanje, M. (2005). Early changes in gene expression in the dorsal root ganglia after transection of the sciatic nerve: Effects of amphiregulin and PAI-1 on regeneration, brain research. Molecular Brain Research, 136, 65–74.
NSCISC. (2013). Spinal cord injury facts and figures at a glance. Journal of Spinal Cord Medicine, 36, 1–2.
Palfi, S. et al. (2014). Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson’s disease: A dose escalation, open-label, phase 1/2 trial. Lancet, 383, 1138–1146.
Parikh, P., Hao, Y., Hosseinkhani, M., Patil, S. B., Huntley, G. W., Tessier-Lavigne, M., et al. (2011). Regeneration of axons in injured spinal cord by activation of bone morphogenetic protein/Smad1 signaling pathway in adult neurons. Proceedings of the National Academy of Sciences of the USA, 108, E99–107.
Park, K. K., Liu, K., Hu, Y., Smith, P. D., Wang, C., Cai, B., et al. (2008). Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science, 322, 963–966.
Pasterkamp, R. J., De, W. F., Holtmaat, A. J., & Verhaagen, J. (1998). Evidence for a role of the chemorepellent semaphorin III and its receptor neuropilin-1 in the regeneration of primary olfactory axons. Journal of Neuroscience, 18, 9962–9976.
Pasterkamp, R. J., Giger, R. J., Ruitenberg, M. J., Holtmaat, A. J., De, W. J., De, W. F., et al. (1999). 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. Molecular and Cellular Neuroscience, 13, 143–166.
Pernet, V., & Schwab, M. E. (2012). The role of Nogo-A in axonal plasticity, regrowth and repair. Cell and Tissue Research, 349, 97–104.
Perry, R. B., Doron-Mandel, E., Iavnilovitch, E., Rishal, I., Dagan, S. Y., Tsoory, M., et al. (2012). Subcellular knockout of importin beta1 perturbs axonal retrograde signaling. Neuron, 75, 294–305.
Pollock, G., Pennypacker, K. R., Memet, S., Israel, A., & Saporta, S. (2005). Activation of NF-kappaB in the mouse spinal cord following sciatic nerve transection. Experimental Brain Research, 165, 470–477.
Post, M. W., & van Leeuwen, C. M. (2012). Psychosocial issues in spinal cord injury: A review. Spinal Cord, 50, 382–389.
Prinjha, R., Moore, S. E., Vinson, M., Blake, S., Morrow, R., Christie, G., et al. (2000). Inhibitor of neurite outgrowth in humans. Nature, 403, 383–384.
Puttagunta, R., Tedeschi, A., Soria, M. G., Hervera, A., Lindner, R., Rathore, K. I., et al. (2014). PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system. Nature Communications, 5, 3527.
Qiu, J., Cafferty, W. B., McMahon, S. B., & Thompson, S. W. (2005). Conditioning injury-induced spinal axon regeneration requires signal transducer and activator of transcription 3 activation. Journal of Neuroscience, 25, 1645–1653.
Quadrato, G., & Di Giovanni, S. (2013). Waking up the sleepers: Shared transcriptional pathways in axonal regeneration and neurogenesis. Cellular and Molecular Life Sciences, 70, 993–1007.
Raineteau, O., Fouad, K., Noth, P., Thallmair, M., & Schwab, M. E. (2001). Functional switch between motor tracts in the presence of the mAb IN-1 in the adult rat. Proceedings of the National Academy of Sciences of the USA, 98, 6929–6934.
Raivich, G., Bohatschek, M., Da, C. C., Iwata, O., Galiano, M., Hristova, M., et al. (2004). The AP-1 transcription factor c-Jun is required for efficient axonal regeneration. Neuron, 43, 57–67.
Raivich, G., & Makwana, M. (2007). The making of successful axonal regeneration: Genes, molecules and signal transduction pathways. Brain Research Reviews, 53, 287–311.
Richardson, P. M., & Issa, V. M. (1984). Peripheral injury enhances central regeneration of primary sensory neurones. Nature, 309, 791–793.
Richardson, P. M., McGuinness, U. M., & Aguayo, A. J. (1982). Peripheral nerve autografts to the rat spinal cord: Studies with axonal tracing methods. Brain Research, 237, 147–162.
Richardson, P. M., & Verge, V. M. (1987). Axonal regeneration in dorsal spinal roots is accelerated by peripheral axonal transection. Brain Research, 411, 406–408.
Rishal, I., & Fainzilber, M. (2010). Retrograde signaling in axonal regeneration. Experimental Neurology, 223, 5–10.
Rossi, F., Gianola, S., & Corvetti, L. (2007). Regulation of intrinsic neuronal properties for axon growth and regeneration. Progress in Neurobiology, 81, 1–28.
Rudge, J. S., & Silver, J. (1990). Inhibition of neurite outgrowth on astroglial scars in vitro. Journal of Neuroscience, 10, 3594–3603.
Russell, D. W. (2007). AAV vectors, insertional mutagenesis, and cancer. Molecular Therapy, 15, 1740–1743.
Saijilafu, H. E., & Zhou, F. Q. (2011). Genetic dissection of axon regeneration via in vivo electroporation of adult mouse sensory neurons. Nature Communications, 2, 543.
Sayer, F. T., Kronvall, E., & Nilsson, O. G. (2006). Methylprednisolone treatment in acute spinal cord injury: The myth challenged through a structured analysis of published literature. The Spine Journal, 6, 335–343.
Schonherr, M. C., Groothoff, J. W., Mulder, G. A., & Eisma, W. H. (1996). Rehabilitation of patients with spinal cord lesions in The Netherlands: An epidemiological study. Spinal Cord, 34, 679–683.
Seijffers, R., Allchorne, A. J., & Woolf, C. J. (2006). The transcription factor ATF-3 promotes neurite outgrowth. Molecular and Cellular Neuroscience, 32, 143–154.
Seijffers, R., Mills, C. D., & Woolf, C. J. (2007). ATF3 increases the intrinsic growth state of DRG neurons to enhance peripheral nerve regeneration. Journal of Neuroscience, 27, 7911–7920.
Simpson, L. A., Eng, J. J., Hsieh, J. T., & Wolfe, D. L. (2012). The health and life priorities of individuals with spinal cord injury: A systematic review. Journal of Neurotrauma, 29, 1548–1555.
Skene, J. H. (1989). Axonal growth-associated proteins. Annual Review of Neuroscience, 12, 127–156.
Skene, J. H., & Willard, M. (1981). Axonally transported proteins associated with axon growth in rabbit central and peripheral nervous systems. Journal of Cell Biology, 89, 96–103.
Smaldone, S., Laub, F., Else, C., Dragomir, C., & Ramirez, F. (2004). Identification of MoKA, a novel F-box protein that modulates Kruppel-like transcription factor 7 activity. Molecular and Cellular Biology, 24, 1058–1069.
Smith, R. P., Lerch-Haner, J. K., Pardinas, J. R., Buchser, W. J., Bixby, J. L., & Lemmon, V. P. (2011). Transcriptional profiling of intrinsic PNS factors in the postnatal mouse. Molecular and Cellular Neuroscience, 46, 32–44.
Smith, P. D., Sun, F., Park, K. K., Cai, B., Wang, C., Kuwako, K., et al. (2009). SOCS3 deletion promotes optic nerve regeneration in vivo. Neuron, 64, 617–623.
Soderblom, C., Luo, X., Blumenthal, E., Bray, E., Lyapichev, K., Ramos, J., et al. (2013). Perivascular fibroblasts form the fibrotic scar after contusive spinal cord injury. Journal of Neuroscience, 33, 13882–13887.
Sommervaille, T., Reynolds, M. L., & Woolf, C. J. (1991). Time-dependent differences in the increase in GAP-43 expression in dorsal root ganglion cells after peripheral axotomy. Neuroscience, 45, 213–220.
Spanevello, M. D., Tajouri, S. I., Mirciov, C., Kurniawan, N., Pearse, M. J., Fabri, L. J., et al. (2013). Acute delivery of EphA4-Fc improves functional recovery after contusive spinal cord injury in rats. Journal of Neurotrauma, 30, 1023–1034.
Stam, F. J., Macgillavry, H. D., Armstrong, N. J., de Gunst, M. C., Zhang, Y., Van Kesteren, R. E., et al. (2007). Identification of candidate transcriptional modulators involved in successful regeneration after nerve injury. European Journal of Neuroscience, 25, 3629–3637.
Stam, F. J., Mason, M. R. J., Smit, A. B., Verhaagen, J. (2008). A meta-analysis of large-scale gene expression studies of the injured PNS: Toward the genetic networks that govern successful regeneration. In: Neural degeneration and repair: Gene expression profiling, proteomics and systems biology (Müller HW, ed), pp 35–59.
Storek, B., Harder, N. M., Banck, M. S., Wang, C., McCarty, D. M., Janssen, W. G., et al. (2006). Intrathecal long-term gene expression by self-complementary adeno-associated virus type 1 suitable for chronic pain studies in rats. Molecular Pain, 2, 4.
Sun, F., Park, K. K., Belin, S., Wang, D., Lu, T., Chen, G., et al. (2011). Sustained axon regeneration induced by co-deletion of PTEN and SOCS3. Nature, 480, 372–375.
Sun, H., Xu, J., Della Penna, K. B., Benz, R. J., Kinose, F., Holder, D. J., et al. (2002). Dorsal horn-enriched genes identified by DNA microarray, in situ hybridization and immunohistochemistry. BMC Neuroscience, 3, 11.
Tan, C. L., Andrews, M. R., Kwok, J. C., Heintz, T. G., Gumy, L. F., Fassler, R., et al. (2012). Kindlin-1 enhances axon growth on inhibitory chondroitin sulfate proteoglycans and promotes sensory axon regeneration. Journal of Neuroscience, 32, 7325–7335.
Tanabe, K., Bonilla, I., Winkles, J. A., & Strittmatter, S. M. (2003). Fibroblast growth factor-inducible-14 is induced in axotomized neurons and promotes neurite outgrowth. Journal of Neuroscience, 23, 9675–9686.
Tator, C. H. (1996). Experimental and clinical studies of the pathophysiology and management of acute spinal cord injury. Journal of Spinal Cord Medicine, 19, 206–214.
Tester, N. J., & Howland, D. R. (2008). Chondroitinase ABC improves basic and skilled locomotion in spinal cord injured cats. Experimental Neurology, 209, 483–496.
Tetzlaff, W., Alexander, S. W., Miller, F. D., & Bisby, M. A. (1991). Response of facial and rubrospinal neurons to axotomy: Changes in mRNA expression for cytoskeletal proteins and GAP-43. Journal of Neuroscience, 11, 2528–2544.
Thallmair, M., Metz, G. A., Z’Graggen, W. J., Raineteau, O., Kartje, G. L., & Schwab, M. E. (1998). Neurite growth inhibitors restrict plasticity and functional recovery following corticospinal tract lesions. Nature Neuroscience, 1, 124–131.
Tom, V. J., & Houle, J. D. (2008). Intraspinal microinjection of chondroitinase ABC following injury promotes axonal regeneration out of a peripheral nerve graft bridge. Experimental Neurology, 211, 315–319.
Towne, C., & Aebischer, P. (2009). Lentiviral and adeno-associated vector-based therapy for motor neuron disease through RNAi. Methods in Molecular Biology, 555, 87–108.
Towne, C., Pertin, M., Beggah, A. T., Aebischer, P., & Decosterd, I. (2009). Recombinant adeno-associated virus serotype 6 (rAAV2/6)-mediated gene transfer to nociceptive neurons through different routes of delivery. Molecular Pain, 5, 52.
Trakhtenberg, E. F., & Goldberg, J. L. (2012). Epigenetic regulation of axon and dendrite growth. Frontiers in Molecular Neuroscience, 5, 24.
van den Berg, M. E., Castellote, J. M., Mahillo-Fernandez, I., & de Pedro-Cuesta, J. (2010). Incidence of spinal cord injury worldwide: A systematic review. Neuroepidemiology, 34, 184–192.
van der Putten, J. J., Stevenson, V. L., Playford, E. D., & Thompson, A. J. (2001). Factors affecting functional outcome in patients with nontraumatic spinal cord lesions after inpatient rehabilitation. Neurorehabil Neural Repair, 15, 99–104.
Van Kesteren, R. E., Mason, M. R., Macgillavry, H. D., Smit, A. B., & Verhaagen, J. (2011). A gene network perspective on axonal regeneration. Frontiers in Molecular Neuroscience, 4, 46.
Varma, A. K., Das, A., Wallace, G., Barry, J., Vertegel, A. A., Ray, S. K., et al. (2013). Spinal cord injury: A review of current therapy, future treatments, and basic science frontiers. Neurochemical Research, 38, 895–905.
Verhaagen, J., Van Kesteren, R. E., Bossers, K. A., Macgillavry, H. D., Mason, M. R., & Smit, A. B. (2012). Molecular target discovery for neural repair in the functional genomics era. Handbook of Clinical Neurology, 109, 595–616.
Wang, D., Ichiyama, R. M., Zhao, R., Andrews, M. R., & Fawcett, J. W. (2011). Chondroitinase combined with rehabilitation promotes recovery of forelimb function in rats with chronic spinal cord injury. Journal of Neuroscience, 31, 9332–9344.
Wang, K. C., Koprivica, V., Kim, J. A., Sivasankaran, R., Guo, Y., Neve, R. L., et al. (2002). Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature, 417, 941–944.
Wang, J. T., Kunzevitzky, N. J., Dugas, J. C., Cameron, M., Barres, B. A., & Goldberg, J. L. (2007). Disease gene candidates revealed by expression profiling of retinal ganglion cell development. Journal of Neuroscience, 27, 8593–8603.
Werner, A., Willem, M., Jones, L. L., Kreutzberg, G. W., Mayer, U., & Raivich, G. (2000). Impaired axonal regeneration in alpha7 integrin-deficient mice. Journal of Neuroscience, 20, 1822–1830.
Westphal, M., Yla-Herttuala, S., Martin, J., Warnke, P., Menei, P., Eckland, D., et al. (2013). Adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir for patients with operable high-grade glioma (ASPECT): A randomised, open-label, phase 3 trial. Lancet Oncology, 14, 823–833.
Wong, L. F., Yip, P. K., Battaglia, A., Grist, J., Corcoran, J., Maden, M., et al. (2006). Retinoic acid receptor beta2 promotes functional regeneration of sensory axons in the spinal cord. Nature Neuroscience, 9, 243–250.
Wu, D., Zhang, Y., Bo, X., Huang, W., Xiao, F., Zhang, X., et al. (2007). Actions of neuropoietic cytokines and cyclic AMP in regenerative conditioning of rat primary sensory neurons. Experimental Neurology, 204, 66–76.
Wujek, J. R., & Lasek, R. J. (1983). Correlation of axonal regeneration and slow component B in two branches of a single axon. Journal of Neuroscience, 3, 243–251.
Xiao, H. S., Huang, Q. H., Zhang, F. X., Bao, L., Lu, Y. J., Guo, C., et al. (2002). Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain. Proceedings of the National Academy of Sciences of the USA, 99, 8360–8365.
Xu, Y., Gu, Y., Wu, P., Li, G. W., & Huang, L. Y. (2003). Efficiencies of transgene expression in nociceptive neurons through different routes of delivery of adeno-associated viral vectors. Human Gene Therapy, 14, 897–906.
Yip, P. K., Wong, L. F., Sears, T. A., Yanez-Munoz, R. J., & McMahon, S. B. (2010). Cortical overexpression of neuronal calcium sensor-1 induces functional plasticity in spinal cord following unilateral pyramidal tract injury in rat. PLoS Biology, 8, e1000399.
Zhao, R. R., Andrews, M. R., Wang, D., Warren, P., Gullo, M., Schnell, L., et al. (2013). Combination treatment with anti-Nogo-A and chondroitinase ABC is more effective than single treatments at enhancing functional recovery after spinal cord injury. European Journal of Neuroscience, 38, 2946–2961.
Zhao, R. R., & Fawcett, J. W. (2013). Combination treatment with chondroitinase ABC in spinal cord injury–breaking the barrier. Neuroscience Bulletin, 29, 477–483.
Zou, H., Ho, C., Wong, K., & Tessier-Lavigne, M. (2009). Axotomy-induced Smad1 activation promotes axonal growth in adult sensory neurons. Journal of Neuroscience, 29, 7116–7123.
Acknowledgments
The authors acknowledge the editorial help of Dr. Matthew Mason.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Fagoe, N.D., van Heest, J. & Verhaagen, J. Spinal Cord Injury and the Neuron-Intrinsic Regeneration-Associated Gene Program. Neuromol Med 16, 799–813 (2014). https://doi.org/10.1007/s12017-014-8329-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12017-014-8329-3