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The Journal of Neuroscience, April 15, 2001, 21(8):2651-2660
Two-Tiered Inhibition of Axon Regeneration at the Dorsal Root Entry Zone
Matt S. Ramer1, 2, Ishwari Duraisingam1, John V. Priestley2, and Stephen B. McMahon1 1 Sensory Function Group, Center for Neuroscience Research, Guy's King's and St. Thomas' School of Biomedical Science, London SE1 1UL, United Kingdom, and 2 Neuroscience Section, Division of Biomedical Science, St. Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, London E1 4NS, United Kingdom
Glial-derived inhibitory molecules and a weak cell-body response prevent sensory axon regeneration into the spinal cord after dorsal root injury. Neurotrophic factors, particularly neurotrophin-3 (NT-3), may increase the regenerative capacity of sensory neurons after dorsal rhizotomy, allowing regeneration across the dorsal root entry zone (DREZ). Intrathecal NT-3, delivered at the time of injury, promoted an upregulation of the growth-associated protein GAP-43 primarily in large-diameter sensory profiles (which did not occur after rhizotomy alone), as well as regeneration of cholera toxin B-labeled sensory axons across the DREZ and deep into the dorsal horn. However, delaying treatment for 1 week compromised regeneration: although axons still penetrated the DREZ, growth within white matter was qualitatively and quantitatively restricted. This was not associated with an impaired cell-body response (GAP-43 upregulation was equivalent for both immediate and delayed treatments), or with astrogliosis at the DREZ, which begins almost immediately after rhizotomy, but with the delayed appearance of mature ED1-expressing phagocytes in the dorsal white matter between 1 and 2 weeks after lesion, marking the beginning of myelin breakdown. After rhizotomy with immediate NT-3 treatment, regeneration continues beyond 2 weeks, but in the dorsal gray matter rather than in the degenerating dorsal columns. The ability of NT-3 to promote regeneration across the DREZ, but not after the beginning of degeneration after delayed treatment reveals a hierarchy of inhibitory influences: the astrogliotic, but not the degenerative barrier is surmountable by NT-3 treatment.
Key words: neurotrophin-3; regeneration; degeneration; astrocytes; oligodendrocytes; myelin; dorsal root ganglion
Copyright © 2001 Society for Neuroscience 0270-6474/01/2182651-10$05.00/0
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