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Neurotrophins and the neuronal response to axotomy Kobayashi, Nao
Abstract
Unlike facial motoneurons (FMNs), which successfully regenerate after axotomy, rubrospinal neurons (RSNs) undergo a marked atrophy in the second week following cervical axotomy. This delayed atrophy is accompanied by a decline in the expression of regeneration associated genes (RAGs), such as GAP-43 and Ta1-tubulin, which are initially elevated after injury. This observation correlates with the growth of only a small percentage of rubrospinal axons into the permissive environment of a peripheral nerve (PN) implanted into the cord at the level of transection. After low thoracic axotomy, there is no increase in RAG expression which also correlates with complete failure of rubrospinal to regenerate into a PN transplant. The overall hypothesis is that these contrasting outcomes are attributed to differences in availability of trophic support between axotomized FMNs and RSNs. Due to their central roles in the nervous system, this thesis focuses on neurotrophins and their receptors. In situ hybridization and reverse transcription-polymerase chain reaction reveal that intact FMNs as well as RSNs express receptor tyrosine kinase(trk) B, a receptor for brain-derived neurotrophic factor (BDNF) and neurotrophin(NT)-4/5, and low level of trkC, a preferred receptor for NT-3, but little trkA. After facial nerve transection, FMNs markedly increase the expression of BDNF and trkB. Whereas this increase is not seen in RSNs after cervical axotomy, supporting the concept that axotomized RSNs receive limited trophic support. These observations lead to the further hypothesis that axotomized RSNs will be responsive to exogenous application of BDNF, NT4/5 or NT-3 based on the trk receptor expression profiles. Application of BDNF or NT-4/5 fully prevents atrophy of RSNs and a decline in the expression of GAP-43 and Ta1-tubulin after cervical injury. Moreover, there is a 3 fold increase in numbers of regenerating RSNs into the PN transplants. Even after thoracic axotomy, BDNF infusion stimulates the expression of GAP-43 and Ta-1 tubulin and overcomes the complete failure of RSNs to regenerate into the PN transplants. This thesis supports the concept that application of an appropriate trophic factor promotes regenerative propensity of injured CNS neurons and provides insights for a development of therapeutic strategies after spinal cord injury.
Item Metadata
Title |
Neurotrophins and the neuronal response to axotomy
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
1998
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Description |
Unlike facial motoneurons (FMNs), which successfully regenerate after axotomy,
rubrospinal neurons (RSNs) undergo a marked atrophy in the second week following
cervical axotomy. This delayed atrophy is accompanied by a decline in the expression of
regeneration associated genes (RAGs), such as GAP-43 and Ta1-tubulin, which are
initially elevated after injury. This observation correlates with the growth of only a small
percentage of rubrospinal axons into the permissive environment of a peripheral nerve
(PN) implanted into the cord at the level of transection. After low thoracic axotomy,
there is no increase in RAG expression which also correlates with complete failure of
rubrospinal to regenerate into a PN transplant. The overall hypothesis is that these
contrasting outcomes are attributed to differences in availability of trophic support
between axotomized FMNs and RSNs. Due to their central roles in the nervous system,
this thesis focuses on neurotrophins and their receptors. In situ hybridization and
reverse transcription-polymerase chain reaction reveal that intact FMNs as well as RSNs
express receptor tyrosine kinase(trk) B, a receptor for brain-derived neurotrophic factor
(BDNF) and neurotrophin(NT)-4/5, and low level of trkC, a preferred receptor for NT-3,
but little trkA. After facial nerve transection, FMNs markedly increase the expression of
BDNF and trkB. Whereas this increase is not seen in RSNs after cervical axotomy,
supporting the concept that axotomized RSNs receive limited trophic support. These
observations lead to the further hypothesis that axotomized RSNs will be responsive to
exogenous application of BDNF, NT4/5 or NT-3 based on the trk receptor expression
profiles. Application of BDNF or NT-4/5 fully prevents atrophy of RSNs and a decline in
the expression of GAP-43 and Ta1-tubulin after cervical injury. Moreover, there is a 3
fold increase in numbers of regenerating RSNs into the PN transplants. Even after thoracic axotomy, BDNF infusion stimulates the expression of GAP-43 and Ta-1 tubulin
and overcomes the complete failure of RSNs to regenerate into the PN transplants. This
thesis supports the concept that application of an appropriate trophic factor promotes
regenerative propensity of injured CNS neurons and provides insights for a development
of therapeutic strategies after spinal cord injury.
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Extent |
18263521 bytes
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Genre | |
Type | |
File Format |
application/pdf
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Language |
eng
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Date Available |
2009-06-22
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Provider |
Vancouver : University of British Columbia Library
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Rights |
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.
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DOI |
10.14288/1.0099392
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
1998-11
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Campus | |
Scholarly Level |
Graduate
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Aggregated Source Repository |
DSpace
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Item Media
Item Citations and Data
Rights
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.