FOXO3a as a sensor of unilateral nerve injury in sensory neurons ipsilateral, contralateral and remote to injury
Emerging evidence supports that the stress response to peripheral nerve injury extends beyond the injured neuron, with alterations in associated transcription factors detected both locally and remote to the lesion. Stress-induced nuclear translocation of the transcription factor forkhead class box O...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wolters Kluwer Medknow Publications
2020-01-01
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| Series: | Neural Regeneration Research |
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| Online Access: | http://www.nrronline.org/article.asp?issn=1673-5374;year=2020;volume=15;issue=12;spage=2353;epage=2361;aulast=Hasmatali |
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| author | Jovan C.D. Hasmatali Jolly De Guzman Jayne M Johnston Hossein Noyan Bernhard H Juurlink Vikram Misra Valerie M.K. Verge |
| author_facet | Jovan C.D. Hasmatali Jolly De Guzman Jayne M Johnston Hossein Noyan Bernhard H Juurlink Vikram Misra Valerie M.K. Verge |
| author_sort | Jovan C.D. Hasmatali |
| collection | DOAJ |
| description | Emerging evidence supports that the stress response to peripheral nerve injury extends beyond the injured neuron, with alterations in associated transcription factors detected both locally and remote to the lesion. Stress-induced nuclear translocation of the transcription factor forkhead class box O3a (FOXO3a) was initially linked to activation of apoptotic genes in many neuronal subtypes. However, a more complex role of FOXO3a has been suggested in the injury response of sensory neurons, with the injured neuron expressing less FOXO3a. To elucidate this response and test whether non-injured sensory neurons also alter FOXO3a expression, the temporal impact of chronic unilateral L4–6 spinal nerve transection on FOXO3a expression and nuclear localization in adult rat dorsal root ganglion neurons ipsilateral, contralateral or remote to injury relative to naïve controls was examined. In naïve neurons, high cytoplasmic and nuclear levels of FOXO3a colocalized with calcitonin gene related peptide, a marker of the nociceptive subpopulation. One hour post-injury, an acute increase in nuclear FOXO3a in small size injured neurons occurred followed by a significant decrease after 1, 2 and 4 days, with levels increasing toward pre-injury levels by 1 week post-injury. A more robust biphasic response to the injury was observed in uninjured neurons contralateral to and those remote to injury. Nuclear levels of FOXO3a peaked at 1 day, decreased by 4 days, then increased by 1 week post-injury, a response mirrored in C4 dorsal root ganglion neurons remote to injury. This altered expression contralateral and remote to injury supports that spinal nerve damage has broader systemic impacts, a response we recently reported for another stress transcription factor, Luman/CREB3. The early decreased expression and nuclear localization of FOXO3a in the injured neuron implicate these changes in the cell body response to injury that may be protective. Finally, the broader systemic changes support the existence of stress/injury-induced humeral factor(s) influencing transcriptional and potentially behavioral changes in uninjured dorsal root ganglion neurons. Approval to conduct this study was obtained from the University of Saskatchewan Animal Research Ethics Board (protocol #19920164). |
| first_indexed | 2024-12-13T12:41:42Z |
| format | Article |
| id | doaj.art-b53d84e889d84727b8b6116b67c5be86 |
| institution | Directory Open Access Journal |
| issn | 1673-5374 |
| language | English |
| last_indexed | 2024-12-13T12:41:42Z |
| publishDate | 2020-01-01 |
| publisher | Wolters Kluwer Medknow Publications |
| record_format | Article |
| series | Neural Regeneration Research |
| spelling | doaj.art-b53d84e889d84727b8b6116b67c5be862022-12-21T23:45:38ZengWolters Kluwer Medknow PublicationsNeural Regeneration Research1673-53742020-01-0115122353236110.4103/1673-5374.284999FOXO3a as a sensor of unilateral nerve injury in sensory neurons ipsilateral, contralateral and remote to injuryJovan C.D. HasmataliJolly De GuzmanJayne M JohnstonHossein NoyanBernhard H JuurlinkVikram MisraValerie M.K. VergeEmerging evidence supports that the stress response to peripheral nerve injury extends beyond the injured neuron, with alterations in associated transcription factors detected both locally and remote to the lesion. Stress-induced nuclear translocation of the transcription factor forkhead class box O3a (FOXO3a) was initially linked to activation of apoptotic genes in many neuronal subtypes. However, a more complex role of FOXO3a has been suggested in the injury response of sensory neurons, with the injured neuron expressing less FOXO3a. To elucidate this response and test whether non-injured sensory neurons also alter FOXO3a expression, the temporal impact of chronic unilateral L4–6 spinal nerve transection on FOXO3a expression and nuclear localization in adult rat dorsal root ganglion neurons ipsilateral, contralateral or remote to injury relative to naïve controls was examined. In naïve neurons, high cytoplasmic and nuclear levels of FOXO3a colocalized with calcitonin gene related peptide, a marker of the nociceptive subpopulation. One hour post-injury, an acute increase in nuclear FOXO3a in small size injured neurons occurred followed by a significant decrease after 1, 2 and 4 days, with levels increasing toward pre-injury levels by 1 week post-injury. A more robust biphasic response to the injury was observed in uninjured neurons contralateral to and those remote to injury. Nuclear levels of FOXO3a peaked at 1 day, decreased by 4 days, then increased by 1 week post-injury, a response mirrored in C4 dorsal root ganglion neurons remote to injury. This altered expression contralateral and remote to injury supports that spinal nerve damage has broader systemic impacts, a response we recently reported for another stress transcription factor, Luman/CREB3. The early decreased expression and nuclear localization of FOXO3a in the injured neuron implicate these changes in the cell body response to injury that may be protective. Finally, the broader systemic changes support the existence of stress/injury-induced humeral factor(s) influencing transcriptional and potentially behavioral changes in uninjured dorsal root ganglion neurons. Approval to conduct this study was obtained from the University of Saskatchewan Animal Research Ethics Board (protocol #19920164).http://www.nrronline.org/article.asp?issn=1673-5374;year=2020;volume=15;issue=12;spage=2353;epage=2361;aulast=Hasmatalicell body response; contralateral response; dorsal root ganglion; peripheral nerve injury; plasticity; sciatic nerve; sensory neuron; stress; systemic; transcription factor; unilateral peripheral nerve injury |
| spellingShingle | Jovan C.D. Hasmatali Jolly De Guzman Jayne M Johnston Hossein Noyan Bernhard H Juurlink Vikram Misra Valerie M.K. Verge FOXO3a as a sensor of unilateral nerve injury in sensory neurons ipsilateral, contralateral and remote to injury Neural Regeneration Research cell body response; contralateral response; dorsal root ganglion; peripheral nerve injury; plasticity; sciatic nerve; sensory neuron; stress; systemic; transcription factor; unilateral peripheral nerve injury |
| title | FOXO3a as a sensor of unilateral nerve injury in sensory neurons ipsilateral, contralateral and remote to injury |
| title_full | FOXO3a as a sensor of unilateral nerve injury in sensory neurons ipsilateral, contralateral and remote to injury |
| title_fullStr | FOXO3a as a sensor of unilateral nerve injury in sensory neurons ipsilateral, contralateral and remote to injury |
| title_full_unstemmed | FOXO3a as a sensor of unilateral nerve injury in sensory neurons ipsilateral, contralateral and remote to injury |
| title_short | FOXO3a as a sensor of unilateral nerve injury in sensory neurons ipsilateral, contralateral and remote to injury |
| title_sort | foxo3a as a sensor of unilateral nerve injury in sensory neurons ipsilateral contralateral and remote to injury |
| topic | cell body response; contralateral response; dorsal root ganglion; peripheral nerve injury; plasticity; sciatic nerve; sensory neuron; stress; systemic; transcription factor; unilateral peripheral nerve injury |
| url | http://www.nrronline.org/article.asp?issn=1673-5374;year=2020;volume=15;issue=12;spage=2353;epage=2361;aulast=Hasmatali |
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