Influence of the axotomy to cell body distance in rat rubrospinal and spinal motoneurons: Differential regulation of GAP-43, tubulins, and neurofilament-M

Fernandes, Karl J.L.; Fan, Da-Peng; Tsui, Britney; Cassar, S.L.; Tetzlaff, Wolfram

doi:10.1002/(sici)1096-9861(19991129)414:4<495::aid-cne6>3.0.co;2-s

Cited by 168 publications

(136 citation statements)

References 76 publications

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“…Proximal axotomies are linked to altered expression of growth-associated proteins such as GAP-43, ␣-tubulins, and neurofilament-m (Fernandes et al, 1999) and are associated with increased axonal growth capacity . We have previously shown that PCIs are proximally axotomized and express GAP-43 after a midline lesion (Fenrich et al, 2007).…”

Section: Regeneration Despite Inhibitionmentioning

confidence: 99%

Spinal Interneuron Axons Spontaneously Regenerate after Spinal Cord Injury in the Adult Feline

Fenrich¹,

Rose²

2009

J. Neurosci.

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It is well established that long, descending axons of the adult mammalian spinal cord do not regenerate after a spinal cord injury (SCI). These axons do not regenerate because they do not mount an adequate regenerative response and growth is inhibited at the injury site by growth cone collapsing molecules, such as chondroitin sulfate proteoglycans (CSPGs). However, whether axons of axotomized spinal interneurons regenerate through the inhibitory environment of an SCI site remains unknown. Here, we show that cut axons from adult mammalian spinal interneurons can regenerate through an SCI site and form new synaptic connections in vivo. Using morphological and immunohistochemical analyses, we found that after a midsagittal transection of the adult feline spinal cord, axons of propriospinal commissural interneurons can grow across the lesion despite a close proximity of their growth cones to CSPGs. Furthermore, using immunohistochemical and electrophysiological analyses, we found that the regenerated axons conduct action potentials and form functional synaptic connections with motoneurons, thus providing new circuits that cross the transected commissures. Our results show that interneurons of the adult mammalian spinal cord are capable of spontaneous regeneration after injury and suggest that elucidating the mechanisms that allow these axons to regenerate may lead to useful new therapeutic strategies for restoring function after injury to the adult CNS.

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Section: Regeneration Despite Inhibitionmentioning

confidence: 99%

Spinal Interneuron Axons Spontaneously Regenerate after Spinal Cord Injury in the Adult Feline

Fenrich¹,

Rose²

2009

J. Neurosci.

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“…There are several possible reasons for this disparity: first, manipulations associated with DRG dissociation and microinjection render the transplanted neurons less susceptible to inhibitory factors present in the degenerating dorsal columns; second, the different regenerative responses might relate to the amount of axon lost (in the Davies experiments all of the axon was removed). In several systems the regenerative response is augmented with increasing proximity of the lesion to the cell body (Mathew and Miller 1993;Fernandes et al, 1999). Other differences may include the differing glial elements encountered by regenerating axons along their course (after rhizotomy for example, axons must transit from Schwann cells to astrocytes), or temporal aspects: with delayed treatment, the axons would have been stopped for several days, possibly altering the extent to which they are capable of responding to NT-3 (although the equivalent upregulation of GAP-43 in immediately and belatedly treated rats would suggest otherwise).…”

Section: Barrier Two: Frank Degenerationmentioning

confidence: 99%

Two-Tiered Inhibition of Axon Regeneration at the Dorsal Root Entry Zone

Ramer

Duraisingam²,

Priestley

et al. 2001

J. Neurosci.

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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 ganglionThe differential abilities of peripheral and central nervous tissue to support regeneration is exemplified at the dorsal root entry zone (DREZ), which marks the entry point of primary afferent axons into the spinal cord. Here, the environment changes abruptly from consisting of growth-permissive Schwann cells, to astrocytes, oligodendrocytes, and microglia, which may all inhibit regeneration (Fawcett and Asher, 1999). On contact with the DREZ, regenerating axons form club-like end bulbs or synapselike structures, (Ramon y Cajal, 1928;Carlstedt, 1985), but because of the prohibitive environment of the CNS and a paltry regenerative response of sensory neurons to rhizotomy, they never re-enter the adult cord.One strategy to encourage regeneration is to enhance the growth response of the rhizotomized neurons. GAP-43 is induced in nearly all neurons during peripheral nerve regeneration (Verge et al., 1990b), but in few neurons after rhizotomy (Schreyer and Skene, 1993), unless the root is severed very close to the DRG (Chong et al., 1996). Dorsal root axonal growth occurs at about half the rate of peripheral axons (Wujek and Lasek, 1983;Oblinger and Lasek, 1984). An experimental "conditioning" lesion to a peripheral nerve before dorsal rhizotomy doubles the rate of ...

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“…Although axotomy close to the cell body can produce a more robust (2,10,19,45) or faster (45) regenerative response, this is doubtful in the present study. The distance to the cell body is not as different between the two conditions as it might first seem.…”

Section: What Accounts For State-dependent Axonal Growth Plasticity?mentioning

confidence: 61%

Growth dynamics and morphology of regenerating optic fibers in tectum are altered by injury conditions: An in vivo imaging study in goldfish

Dawson

Meyer

2008

Experimental Neurology

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The dynamic behavior of axons in systems that normally regenerate may provide clues for promoting regeneration in humans. When the optic nerve is severed in adult goldfish, all axons regenerate back to the tectum to reestablish accurate connections. In adult mammals, regeneration can be induced in optic and other axons but typically few fibers regrow and only for short distances. These conditions were mimicked in the adult goldfish by surgically deflecting 10-20% of optic fibers from one tectum into the opposite tectum which was denervated of all other optic fibers by removing its corresponding eye. At 21-63 days, DiI was microinjected into retina to label a few fibers and the fibers were visualized in the living fish for up to 5-7 hours. The dynamic behavior and morphology of these regenerating deflected fibers were analyzed and compared to those regenerating following optic nerve crush. At 3-4 weeks, deflected fibers were found to form more branches and to maintain many more branches than crushed fibers. Although both deflected and crushed fibers exhibited stochastic growth and retraction, deflected fibers spent more time growing but grew for less distance. At 2 months, both deflected and crushed fibers became much more stable. These results show the morphology and behavior of fibers regenerating into the same target tissue can be substantially altered by the injury conditions, that is, they show state dependent plasticity. The morphology and behavior of the deflected fibers suggests they were impaired in their capacity to grow to their correct targets.

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Influence of the axotomy to cell body distance in rat rubrospinal and spinal motoneurons: Differential regulation of GAP-43, tubulins, and neurofilament-M

Cited by 168 publications

References 76 publications

Spinal Interneuron Axons Spontaneously Regenerate after Spinal Cord Injury in the Adult Feline

Spinal Interneuron Axons Spontaneously Regenerate after Spinal Cord Injury in the Adult Feline

Two-Tiered Inhibition of Axon Regeneration at the Dorsal Root Entry Zone

Growth dynamics and morphology of regenerating optic fibers in tectum are altered by injury conditions: An in vivo imaging study in goldfish

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