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JNK/c-Jun Signaling and Peripheral Nerve Regeneration

Lindwall, Charlotta LU (2005)
Abstract
The events associated with axonal injury in the peripheral nervous system (PNS) have been described in detail. However, the molecular mechanisms underlying the regenerative response, or neuronal cell death, following axonal injury are poorly understood. This thesis concerns one such molecular mechanism, JNK-mediated c-Jun activation, in peripheral sensory and sympathetic neurons. By immunohistochemistry, we demonstrate that the transcription factor c-Jun is rapidly activated by the mitogen activated protein kinase (MAPK) JNK, in both sensory and sympathetic neurons after axonal injury. Prevention of c-Jun activation with JNK inhibitors revealed that this activation is associated with survival and axonal outgrowth of developing sensory and... (More)
The events associated with axonal injury in the peripheral nervous system (PNS) have been described in detail. However, the molecular mechanisms underlying the regenerative response, or neuronal cell death, following axonal injury are poorly understood. This thesis concerns one such molecular mechanism, JNK-mediated c-Jun activation, in peripheral sensory and sympathetic neurons. By immunohistochemistry, we demonstrate that the transcription factor c-Jun is rapidly activated by the mitogen activated protein kinase (MAPK) JNK, in both sensory and sympathetic neurons after axonal injury. Prevention of c-Jun activation with JNK inhibitors revealed that this activation is associated with survival and axonal outgrowth of developing sensory and sympathetic neurons. In adult sensory neurons, c-Jun activation is not required for survival, although it is required for axonal outgrowth. Additionally, c-Jun forms dimers with other transcription factors and it is plausible that the expression of these dimerization partners could regulate the physiological effect of c-Jun activation. We found that the activating transcription factor 3 (ATF3) was induced upon axonal injury in sensory and sympathetic neurons and that it colocalized with activated c-Jun. Consequently, we speculate that c-Jun/ATF3 dimers could be important for the regenerative response of peripheral neurons. Such dimers could promote a survival response in neurons under stress situations by inducing the expression of anti-apoptotic proteins such as heat shock protein 27 (Hsp27). We also made attempts to unravel the mechanism by which information of a distal axonal injury is conveyed to the cell body. We demonstrate that components of the JNK signaling pathway are axonally transported from the injury site to the cell body of dorsal root ganglia (DRG) sensory neurons, and also that this transport may contribute to the nuclear increase in c-Jun activity. Hence, we suggest that axonal transport of JNK signaling components could be involved in the transmission of injury information. Furthermore, since c-Jun activation may depend on deprivation of target-derived trophic factors, which is one consequence of axotomy, we analyzed the effect of nerve growth factor (NGF) on c-Jun activation in sensory and sympathetic neurons. NGF did not affect c-Jun activation in embryonic and adult sensory neurons, but it did affect c-Jun activation in neonatal sensory and sympathetic neurons. In conclusion, c-Jun activation seems to be a general neuronal response to peripheral nerve injury, and this response is associated with survival and regeneration. (Less)
Abstract (Swedish)
Popular Abstract in Swedish

De generella företeelser som sker i samband med en axonal skada i det perifera nervsystemet (PNS) har tidigare beskrivits i detalj. Däremot är de molekylära mekanismer som ligger bakom celldöd, eller bakom nervcellens förmåga att regenerera efter en axonal skada, ringa studerade. Den här avhandlingen behandlar en sådan molekylär mekanism, JNK-medierad aktivering av c-Jun, i perifera sensoriska och sympatiska nervceller. Med immunohistokemi har vi visat att transkriptionsfaktorn c-Jun snabbt aktiveras av ett mitogen activated protein kinase (MAPK), kallat JNK, i både sensoriska och sympatiska nervceller efter skada. Genom att hindra denna aktivering av c-Jun med JNK-inhibitorer, visade vi även att... (More)
Popular Abstract in Swedish

De generella företeelser som sker i samband med en axonal skada i det perifera nervsystemet (PNS) har tidigare beskrivits i detalj. Däremot är de molekylära mekanismer som ligger bakom celldöd, eller bakom nervcellens förmåga att regenerera efter en axonal skada, ringa studerade. Den här avhandlingen behandlar en sådan molekylär mekanism, JNK-medierad aktivering av c-Jun, i perifera sensoriska och sympatiska nervceller. Med immunohistokemi har vi visat att transkriptionsfaktorn c-Jun snabbt aktiveras av ett mitogen activated protein kinase (MAPK), kallat JNK, i både sensoriska och sympatiska nervceller efter skada. Genom att hindra denna aktivering av c-Jun med JNK-inhibitorer, visade vi även att aktiveringen var associerad med överlevnad och regeneration hos embryonala och nyfödda sensoriska och sympatiska nervceller. Vuxna nervceller verkar dock inte vara beroende av c-Jun aktivering för överlevnad, men däremot för regeneration. c-Jun har förmågan att bilda dimerer med andra transkriptionsfaktorer och det är möjligt att uttrycket av sådana dimeriserings-partners reglerar den fysiologiska effekten av c-Jun-aktivering. Vi fann att activating transcription factor 3 (ATF3) inducerades som svar på axonal skada i sensoriska och sympatiska nervceller. Vi observerade även att ATF3 var kolokaliserat med c-Jun i dessa nervceller. Således spekulerar vi att dimerer av c-Jun och ATF3 kan vara viktiga för den regenerativa responsen hos skadade perifera nervceller. Sådana dimerer skulle kunna öka överlevnaden vid stress-situationer genom att t.ex. inducera ett uttryck av anti-apoptotiska proteiner som heat shock protein 27 (Hsp27). Vi gjorde även försök för att finna svar på hur information om en distal axonal skada når cellkroppen. Vi visade att komponenter av JNK-signaltransduktionskedjan transporteras i axoner från skadan till cellkroppen i sensoriska nervceller från dorsalrotsganglier (DRG). Vi fann även att sådan transport kan bidra till den skaderelaterade ökade aktiveringen av c-Jun i cellkärnan. Därför föreslår vi att axonal transport av JNK-signalkomponenter kan vara involverade i överföringen av skadeinformation. Eftersom aktiveringen av c-Jun kan vara beroende av förlusten av trofiska faktorer, vilket är en konsekvens av axotomi, undersökte vi effekten av nerve growth factor (NGF) på c-Jun-aktivering i sensoriska och sympatiska nervceller. NGF påverkade inte c-Jun-aktiveringen i embryonala eller i adulta nervceller, men däremot i nyfödda sensoriska och sympatiska nervceller. Slutsatsen av denna avhandling är att c-Jun-aktivering verkar vara ett generellt nervcells-svar på perifer axonal skada och detta svar är associerat med överlevnad och regeneration. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Dr. Med. Herdegen, Thomas, University of Kiel, Department of Pharmacology, Kiel, Germany
organization
publishing date
type
Thesis
publication status
published
subject
keywords
neuropsykologi, neurofysiologi, neurophysiology, Neurologi, neuropsychology, Neurology, Djurfysiologi, Animal physiology, JNK, signal transduction, nerve regeneration
pages
145 pages
publisher
Lund University, Dept. of Cell and Organism Biology
defense location
Department of Cell and Organism Biology, Animal Physiology Building Lecture hall, Helgonavägen 3B, Lund, Sweden
defense date
2005-10-07 09:00:00
ISBN
91-85067-21-0
language
English
LU publication?
yes
additional info
Charlotta Lindwall, Lars Dahlin, Göran Lundborg and Martin Kanje. 2004. Inhibition of c-Jun phosphorylation reduces axonal outgrowth of adult rat nodose ganglia and dorsal root ganglia sensory neurons Molecular and Cellular Neuroscience, vol 27 pp 267-279. Elsevier
Charlotta Lindwall and Martin Kanje. 2005. Retrograde axonal transport of JNK signaling molecules influence injury induced nuclear changes in p-c-Jun and ATF3 in adult rat sensory neurons. Molecular and Cellular Neuroscience, vol 29 pp 269-82. Elsevier
Charlotta Lindwall and Martin Kanje. 2005. The role of p-c-jun in survival and outgrowth of developing sensory neurons. NeuroReport, Lippincott Williams & Wilkins (accepted)
Charlotta Lindwall and Martin Kanje. 2005. The Janus role of c-Jun: Cell death versus survival and regeneration of neonatal sympathetic and sensory neurons Experimental Neurology, Elsevier (accepted)
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Animal Physiology (Closed 2011) (011011000)
id
295bbaf0-a4a7-4be2-b985-01f3bd90c287 (old id 545267)
date added to LUP
2016-04-04 11:15:27
date last changed
2018-11-21 21:03:39
@phdthesis{295bbaf0-a4a7-4be2-b985-01f3bd90c287,
  abstract     = {{The events associated with axonal injury in the peripheral nervous system (PNS) have been described in detail. However, the molecular mechanisms underlying the regenerative response, or neuronal cell death, following axonal injury are poorly understood. This thesis concerns one such molecular mechanism, JNK-mediated c-Jun activation, in peripheral sensory and sympathetic neurons. By immunohistochemistry, we demonstrate that the transcription factor c-Jun is rapidly activated by the mitogen activated protein kinase (MAPK) JNK, in both sensory and sympathetic neurons after axonal injury. Prevention of c-Jun activation with JNK inhibitors revealed that this activation is associated with survival and axonal outgrowth of developing sensory and sympathetic neurons. In adult sensory neurons, c-Jun activation is not required for survival, although it is required for axonal outgrowth. Additionally, c-Jun forms dimers with other transcription factors and it is plausible that the expression of these dimerization partners could regulate the physiological effect of c-Jun activation. We found that the activating transcription factor 3 (ATF3) was induced upon axonal injury in sensory and sympathetic neurons and that it colocalized with activated c-Jun. Consequently, we speculate that c-Jun/ATF3 dimers could be important for the regenerative response of peripheral neurons. Such dimers could promote a survival response in neurons under stress situations by inducing the expression of anti-apoptotic proteins such as heat shock protein 27 (Hsp27). We also made attempts to unravel the mechanism by which information of a distal axonal injury is conveyed to the cell body. We demonstrate that components of the JNK signaling pathway are axonally transported from the injury site to the cell body of dorsal root ganglia (DRG) sensory neurons, and also that this transport may contribute to the nuclear increase in c-Jun activity. Hence, we suggest that axonal transport of JNK signaling components could be involved in the transmission of injury information. Furthermore, since c-Jun activation may depend on deprivation of target-derived trophic factors, which is one consequence of axotomy, we analyzed the effect of nerve growth factor (NGF) on c-Jun activation in sensory and sympathetic neurons. NGF did not affect c-Jun activation in embryonic and adult sensory neurons, but it did affect c-Jun activation in neonatal sensory and sympathetic neurons. In conclusion, c-Jun activation seems to be a general neuronal response to peripheral nerve injury, and this response is associated with survival and regeneration.}},
  author       = {{Lindwall, Charlotta}},
  isbn         = {{91-85067-21-0}},
  keywords     = {{neuropsykologi; neurofysiologi; neurophysiology; Neurologi; neuropsychology; Neurology; Djurfysiologi; Animal physiology; JNK; signal transduction; nerve regeneration}},
  language     = {{eng}},
  publisher    = {{Lund University, Dept. of Cell and Organism Biology}},
  school       = {{Lund University}},
  title        = {{JNK/c-Jun Signaling and Peripheral Nerve Regeneration}},
  year         = {{2005}},
}