Axonal reinjury reveals the survival and re-expression of regeneration-associated genes in chronically axotomized adult mouse motoneurons

McPhail, Lowell T.; Fernandes, Karl J.L.; Chan, Carmen C.M.; Vanderluit, Jacqueline L.; Tetzlaff, Wolfram

doi:10.1016/j.expneurol.2004.04.010

Cited by 47 publications

(43 citation statements)

References 37 publications

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“…Adult axotomized rat facial motor neurons may undergo a slow, nonapoptotic form of degeneration (Moran et al, 2001). Alternatively, at least a fraction of axotomized adult mouse facial motor neurons can survive in a state of extreme atrophy in which they are no longer detectable by Nissl stain (McPhail et al, 2004b). A lack of increased apoptotic cell death has also been observed in the cortex of conditional trkB mutants, despite extensive degeneration (Xu et al, 2000).…”

Section: Long-term Expression Of Truncated Trkb Results In Motor Neurmentioning

confidence: 99%

Long-Term Adeno-Associated Viral Vector-Mediated Expression of Truncated TrkB in the Adult Rat Facial Nucleus Results in Motor Neuron Degeneration

et al. 2006

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Adult facial motor neurons continue to express full-length TrkB tyrosine kinase receptor (TrkB.FL), the high-affinity receptor for the neurotrophins BDNF and neurotrophic factor-4/5 (NT-4/5), suggesting that they remain dependent on target-derived and locally produced neurotrophins in adulthood. Studies on the role of TrkB signaling in the adult CNS have been hampered by the early lethality of bdnf, nt-4/5, and trkB knock-out mice. We disrupted TrkB.FL signaling in adult facial motor neurons using adeno-associated viral vector-mediated overexpression of a naturally occurring dominant-negative TrkB receptor, TrkB.T1. Expression of TrkB.T1 resulted in neuronal atrophy and downregulation of NeuN (neuronal-specific nuclear protein) and ChAT expression in facial motor neurons. A subset of transduced neurons displayed signs of motor neuron degeneration that included dendritic beading and rounding of the soma at 2 months of TrkB.T1 expression. Cell counts revealed a significant reduction in motor neuron number in the facial nucleus at 4 months after onset of expression of TrkB.T1, suggesting that a proportion of TrkB.T1-expressing motor neurons became undetectable as a result of severe atrophy or was lost because of cell death. In contrast, overexpression of TrkB.FL did not result in a decrease in facial motor neuron number. Our results indicate that a subset of facial motor neurons remains dependent on TrkB ligands for the maintenance of structural and molecular characteristics in adulthood.

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Section: Long-term Expression Of Truncated Trkb Results In Motor Neurmentioning

confidence: 99%

Long-Term Adeno-Associated Viral Vector-Mediated Expression of Truncated TrkB in the Adult Rat Facial Nucleus Results in Motor Neuron Degeneration

et al. 2006

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“…The disparity between the two measures of neuronal loss may be due to insufficient sampling of the number of microglial phagocytic clusters, as all post-injury time points were not accounted for. Alternatively, studies by McPhail et al (2004a) suggest that following facial nerve resection, the majority of injured neurons may reside in a shrunken and atrophic state, rendering them undetectable by Nissl staining. Re-injuring the facial nerve resulted in a reversal of neuronal atrophy such that the number of countable neurons increased to 79% of the contralateral side.…”

Section: Discussionmentioning

confidence: 99%

Influence of injury severity on the rate and magnitude of the T lymphocyte and neuronal response to facial nerve axotomy

Ha¹,

Parikh²,

Huang³

et al. 2008

Journal of Neuroimmunology

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The temporal relationship between severity of peripheral axonal injury and T lymphocyte trafficking to the neuronal cell bodies of origin in the brain has been unclear. We sought to test the hypothesis that greater neuronal death induced by disparate forms of peripheral nerve injury would result in differential patterns of T cell infiltration and duration at the cell bodies of origin in the brain and that these measures would correlate with the magnitude of neuronal death over time and cumulative neuronal loss. To test this hypothesis, we compared the time course of CD3 + T cell infiltration and neuronal death (assessed by CD11b + perineuronal microglial phagocytic clusters) following axonal crush versus axonal resection injuries, two extreme variations of facial nerve axotomy that result in mild versus severe neuronal loss, respectively, in the facial motor nucleus. We also quantified the number of facial motor neurons present at 49 days post-injury to determine whether differences in the levels of neuronal death between nerve crush and resection correlated with differences in cumulative neuronal loss. Between 1-7 days post-injury when levels of neuronal death were minimal, we found that the rate of accumulation and magnitude of the T cell response was similar following nerve crush and resection. Differences in the T cell response were apparent by 14 days post-injury when the level of neuronal death following resection was substantially greater than that seen in crush injury. For nerve resection, the peak of neuronal death at 14 days post-resection was followed by a maximal T cell response one week later at 21 days. Differences in the level of neuronal death between the two injuries across the time course tested reflected differences in cumulative neuronal loss at 49 days post-injury. Altogether, these data suggest that the trafficking of T cells to the injured FMN is dependent upon the intensity of peripheral nerve injury and associated neuronal death.

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“…Animals were anesthetized with 4% isoflurane. The right facial nerve was exposed and resected to prevent reconnection of the nerve to its target, as described previously (McPhail, et al, 2004, McPhail, et al, 2005. At 10 weeks post-injury, the nerve was re-exposed and re-injured by removing the neuroma that formed near the proximal nerve stump ("chronic resection + re-injury").…”

Section: Animal Surgerymentioning

confidence: 99%

“…Increasing evidence suggests that in some forms of neuronal injury, neurons may not actually die following nerve injury but reside in an atrophic state, characterized by extreme cell shrinkage and a decreased ability to take up Nissl stain (McPhail, et al, 2004). Recent studies by McPhail et al demonstrated that a population of facial motor neurons undergo a protracted period of degeneration or atrophy following peripheral resection of the facial nerve in adult mice.…”

Section: Introductionmentioning

confidence: 99%

“…Given that a substantial number of facial motor neurons undergo atrophy following axotomy and that the atrophied state of these neurons is reversible by reinjury, T cells may also be involved in mediating the reversal of neuronal atrophy following re-injury. In this study, we therefore used the re-injury model described previously by McPhail et al (2004McPhail et al ( , 2005 to test the hypothesis that the reversal of motor neuron atrophy (i.e., increase in cell number and size) elicited by nerve re-injury would be impaired in immunodeficient recombinase activating gene-2 knockout (RAG-2 KO) mice, which lack mature T and B cells. Neuronal cell counts and mean cell size were compared in mice that received an initial resection of the facial nerve followed by a re-injury of the same nerve 10 weeks later versus mice that received only a single resection followed by a sham re-injury 10 weeks later.…”

Section: Introductionmentioning

confidence: 99%

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Immunodeficiency impairs re-injury induced reversal of neuronal atrophy: Relation to T cell subsets and microglia

Ha¹,

Huang²,

Parikh³

et al. 2007

Experimental Neurology

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Following facial nerve resection in the mouse, a substantial number of neurons reside in an atrophied state (characterized by cell shrinkage and decreased ability to uptake Nissl stain), which can be reversed by re-injury. The mechanisms mediating the reversal of neuronal atrophy remain unclear. Although T cells have been shown to prevent neuronal loss following peripheral nerve injury, it was unknown whether T cells play a role in mediating the reversal of axotomy-induced neuronal atrophy. Thus, we used a facial nerve re-injury model to test the hypothesis that the reversal of neuronal atrophy would be impaired in recombinase activating gene-2 knockout (RAG-2 KO) mice, which lack functional T and B cells. Measures of neuronal survival were compared in the injured facial motor nucleus (FMN) of RAG-2 KO and wild-type (WT) mice that received a resection of the right facial nerve followed by re-injury of the same nerve 10 weeks later ("chronic resection + re-injury") or a resection of the right facial nerve followed by sham re-injury of the same nerve 10 weeks later ("chronic resection + sham"). We recently demonstrated that prior exposure to neuronal injury elicited a marked increase in T cell trafficking indicative of a T cell memory response when the contralateral FMN was injured later in adulthood. We examined if such a T cell memory response would also occur in the current re-injury model. RAG-2 KO mice showed no reversal of neuronal atrophy whereas WT mice showed a robust response. The reversal of atrophy in WT mice was not accompanied by a T cell memory response. Although the number of CD4 + and CD8 + T cells in the injured FMN did not differ from each other, double-negative T cells appear to be recruited in response to neuronal injury. Re-injury did not result in increased expression of MHC2 by microglia. Our findings suggest that T cells may be involved in reversing the axotomy-induced atrophy of injured neurons.

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Axonal reinjury reveals the survival and re-expression of regeneration-associated genes in chronically axotomized adult mouse motoneurons

Cited by 47 publications

References 37 publications

Long-Term Adeno-Associated Viral Vector-Mediated Expression of Truncated TrkB in the Adult Rat Facial Nucleus Results in Motor Neuron Degeneration

Long-Term Adeno-Associated Viral Vector-Mediated Expression of Truncated TrkB in the Adult Rat Facial Nucleus Results in Motor Neuron Degeneration

Influence of injury severity on the rate and magnitude of the T lymphocyte and neuronal response to facial nerve axotomy

Immunodeficiency impairs re-injury induced reversal of neuronal atrophy: Relation to T cell subsets and microglia

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