| 1. |
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| 2. |
- Lindwall Blom, Charlotta, et al.
(författare)
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Nerve Injury-Induced c-Jun Activation in Schwann Cells Is JNK Independent.
- 2014
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Ingår i: BioMed Research International. - : Hindawi Limited. - 2314-6133 .- 2314-6141. ; 2014:Apr 28
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Tidskriftsartikel (refereegranskat)abstract
- We investigated (a) if activation of the mitogen activated protein kinase (MAPK) pathway was linked to the stress activated protein kinase (SAPK) pathway and (b) if JNK was required for activation of c-Jun in Schwann cells of rat sciatic nerve following injury. To this aim, ERK1/2 and the transcription factors c-Jun and ATF-3 were studied by immunohistochemistry in segments of transected nerves. We utilized pharmacological inhibitors of both signal transduction pathways in vitro to determine the effects on downstream signalling events, such as c-Jun activation, and on Schwann cell survival and proliferation. A transection induces c-Jun and ATF-3 transcription in Schwann cells. These events are followed by Schwann cell activation of c-Jun in the injured nerve. The MAPK inhibitor U0126 blocked ERK1/2 activation and reduced Schwann cell proliferation as well as induction of c-Jun transcription. The JNK inhibitor SP600125 reduced Schwann cell proliferation, but did not affect the expression of ERK1/2 or injury-induced increases in c-Jun or ATF-3 levels. Importantly, nerve injury induces Schwann cell activation of c-Jun by phosphorylation, which, in contrast to in sensory neurons, is JNK independent. MAP kinases, other than JNK, can potentially activate c-Jun in Schwann cells following injury; information that is crucial to create new nerve reconstruction strategies.
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| 3. |
- Lindwall, Charlotta, et al.
(författare)
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Inhibition of c-Jun phosphorylation reduces axonal outgrowth of adult rat nodose ganglia and dorsal root ganglia sensory neurons.
- 2004
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Ingår i: Molecular and Cellular Neuroscience. - : Elsevier BV. - 1044-7431. ; 27:3, s. 267-279
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Tidskriftsartikel (refereegranskat)abstract
- The role of c-Jun activation for survival and regeneration of sensory neurons is unclear. Here we report that c-Jun N-terminal kinase (JNK)-mediated c-Jun activation is important for axonal outgrowth of sensory neurons in rat nodose and dorsal root ganglia (DRG). Peripheral severance of the vagus or the sciatic nerve resulted in a massive and rapid, but transient increase of the activated JNK (p-JNK) in neuronal nuclei, followed by c-Jun phosphorylation and activating transcription factor-3 (ATF3) induction. JNK inhibition by the selective JNK inhibitors SP600125 and (D)-JNKI1 did not affect neuronal survival in explanted or dissociated ganglia, but dramatically reduced axonal outgrowth, c-Jun activation, and ATF3 induction. Using retrograde labeling, we demonstrated that activated c-Jun (p-c-Jun) and ATF3 were associated with regenerative neurons. Taken together, our results suggest that JNK-mediated c-Jun activation is one of the first cell body reactions in response to nerve injury and that this activation and subsequent ATF3 induction are associated with axonal outgrowth.
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| 4. |
- Lindwall, Charlotta
(författare)
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JNK/c-Jun Signaling and Peripheral Nerve Regeneration
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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.
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| 5. |
- Lindwall, Charlotta, et al.
(författare)
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Retrograde axonal transport of JNK signaling molecules influence injury induced nuclear changes in p-c-Jun and ATF3 in adult rat sensory neurons
- 2005
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Ingår i: Molecular and Cellular Neuroscience. - : Elsevier BV. - 1044-7431. ; 29:2, s. 269-282
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Tidskriftsartikel (refereegranskat)abstract
- In the present study, we investigated if the previously observed JNK-mediated activation of c-Jun and induction of ATF3 could be ascribed to axonal transport of JNK signaling components, or if axonal transport of the transcription factors themselves contributes to the nuclear changes in injured sensory neurons. We observed retrograde axonal transport of a number of JNK upstream kinases in ligated rat sciatic nerve. In these preparations, axonal transport of JNK/p-JNK, the JNK scaffolding protein JIP, and the transcription factors ATF3 and ATF2/p-ATF2 was also found. No or little retrograde transport of c-Jun and p-c-Jun was found, whereas an anterograde transport of Hsp27, a protein previously reported in the context of p-c-Jun and ATF3, was observed. In separate experiments, we found that in vitro inhibition of axonal transport or axonal inhibition of JNK reduced the number of p-c-Jun- and ATF3-positive neuronal nuclei. The results suggest that retrograde axonal transport of JNK signaling components contributes to the injury induced c-Jun phosphorylation and ATF3 induction.
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| 6. |
- Lindwall, Charlotta, et al.
(författare)
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Selective expression of hyaluronan and receptor for hyaluronan mediated motility (Rhamm) in the adult mouse subventricular zone and rostral migratory stream and in ischemic cortex
- 2013
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Ingår i: Brain Research. - : Elsevier BV. - 0006-8993. ; 1503, s. 62-77
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Tidskriftsartikel (refereegranskat)abstract
- Hyaluronan is a large glycosaminoglycan, which is abundant in the extracellular matrix of the developing rodent brain. In the adult brain however, levels of hyaluronan are significantly reduced. In this study, we used neurocan-GFP as a histochemical probe to analyze the distribution of hyaluronan in the adult mouse subventricular zone (SVZ), as well as in the rostral migratory stream (RMS). Interestingly, we observed that hyaluronan is generally downregulated in the adult brain, but notably remains at high levels in the SVZ and RMS; areas in which neural stem/progenitor cells (NSPCs) persist, proliferate and migrate throughout life. In addition, we found that the receptor for hyaluronan-mediated motility (Rhamm) was expressed in migrating neuroblasts in these areas, indicating that Rhamm could be involved in regulating hyaluronan-mediated cell migration. Hyaluronan levels are balanced by synthesis through hyaluronan synthases (Has) and degradation by hyaluronidases (Hyal). We found that Has1 and Has2, as well as Hyal1 and Hyal2 were expressed in GFAP positive cells in the adult rodent SVZ and RMS, indicating that astrocytes could be regulating hyaluronan-mediated functions in these areas. We also demonstrate that hyaluronan levels are substantially increased at six weeks following a photothrombotic stroke lesion to the adult mouse cortex. Furthermore, GFAP positive cells in the pen-infarct area express Rhamm. Thus, hyaluronan may be involved in regulating cell migration in the normal SVZ and RMS and could also be responsible for priming the peri-infarct area following an ischemic lesion for cell migration. (C) 2013 Elsevier B.V. All rights reserved.
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| 7. |
- Lindwall, Charlotta, et al.
(författare)
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The Janus role of c-Jun: Cell death versus survival and regeneration of neonatal sympathetic and sensory neurons
- 2005
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 196:1, s. 184-194
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the functional outcome of c-Jun activation in sympathetic and sensory neurons of neonatal rat superior cervical ganglion (SCG) and dorsal root ganglion (DRG), respectively. Distinctly different roles of c-Jun activation have been suggested for these two types of neurons. In dissociated sympathetic neurons, c-Jun has been demonstrated to promote apoptosis, whereas in sensory neurons it stimulates axonal outgrowth. In organ-cultured ganglia, we found that c-Jun was activated within 24 h of explantation in both types of neurons, and that the JNK inhibitor SP600125 could mitigate this response. In both types of neurons, c-Jun activation was also reduced by NGF treatment. Inhibition of c-Jun activation did not affect the viability of sympathetic neurons, whereas the number of apoptotic sensory neurons increased. Furthermore, inhibition of c-Jun reduced axonal outgrowth from both SCG and DRG. Thus, in organ culture, c-Jun activation may be required for axonal outgrowth and, at least in sensory neurons, it promotes survival. The role of ATF3, a neuronal marker of injury and a c-Jun dimerization partner, was also examined. We found an ATF3 induction in both SCG and DRG neurons, a response, which was reduced by JNK inhibition. The reduction of ATF3 upon JNK inhibition was much larger in DRG than in SCG, a result which might account for the higher number of apoptotic neurons in JNK inhibitor exposed DRG. Taken together, and contrary to our expectations, neonatal sympathetic and sensory neurons seem to respond to axonal injury similarly with respect to c-Jun activation, and in no case was this activation pro-apoptotic.
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| 8. |
- Lindwall, Charlotta, et al.
(författare)
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The role of p-c-Jun in survival and outgrowth of developing sensory neurons
- 2005
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Ingår i: NeuroReport. - 1473-558X. ; 16:15, s. 1655-1659
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Tidskriftsartikel (refereegranskat)abstract
- c-jun activation has been implicated not only in neuronal apoptosis, but also in survival and regeneration. This Janus facet of c-Jun activation could be related to neuronal cell type or to the developmental stage of the neuron. We investigated c-Jun activation in E18 sensory neurons. Cultures of rat dorsal root ganglia neurons were maintained with or without the addition of nerve growth factor or the c-Jun N-terminal kinase inhibitor, (D)-JNKII. Few dorsal root ganglia neurons survived nerve growth factor deprivation, whereas neurons supplied with nerve growth factor survived and exhibited extensive axonal outgrowth. Activated c-Jun was present in the nuclei of neurons with regenerating axons, but not in apoptotic neurons. c-Jun N-terminal kinase inhibition reduced the number of p-c-Jun immunoreactive and regenerating neurons, and increased cell death. Thus, activation of c-Jun seems to be required for survival and regeneration of developing sensory neurons.
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| 9. |
- Mårtensson, Lisa B., et al.
(författare)
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Ca2+ involvement in activation of extracellular-signalregulated- kinase 1/2 and m-calpain after axotomy of the sciatic nerve
- 2017
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Ingår i: Neural Regeneration Research. - : Medknow. - 1673-5374. ; 12:4, s. 623-628
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Tidskriftsartikel (refereegranskat)abstract
- Detailed mechanisms behind regeneration after nerve injury, in particular signal transduction and the fate of Schwann cells (SCs), are poorly understood. Here, we investigated axotomy-induced activation of extracellular- signal-regulated kinase-1/2 (ERK1/2; important for proliferation) and m-calpain in vitro, and the relation to Ca2+ deletion and Schwann cell proliferation and death after rat sciatic nerve axotomy. Nerve segments were cultured for up to 72 hours with and without ethylene glycol-bis(β-aminoethyl ether)- N,N,N’,N’-tetraacetic acid (EGTA). In some experiments, 5-bromo-2′-deoxyuridine (BrdU) was added during the last 24 hours to detect proliferating cells and propidium iodide (PI) was added at the last hour to detect dead and/or dying cells. Immunohistochemistry of sections of the cultured nerve segments was performed to label m-calpain and the phosphorylated and activated form of ERK1/2. The experiments revealed that immunoreactivity for p-ERK1/2 increased with time in organotypically cultured SCs. p-ERK1/2 and m-calpain were also observed in axons. A significant increase in the number of dead or dying SCs was observed in nerve segments cultured for 24 hours. When deprived of Ca2+, activation of axonal m-calpain was reduced, whereas p-ERK1/2 was increased in SCs. Ca2+ deprivation also significantly reduced the number of proliferating SCs, and instead increased the number of dead or dying SCs. Ca2+ seems to play an important role in activation of ERK1/2 in SCs and in SC survival and proliferation. In addition, extracellular Ca2+ levels are also required for m-calpain activation and up-regulation in axons. Thus, regulation of Ca2+ levels is likely to be a useful method to promote SC proliferation.
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| 10. |
- Persson, Åsa, 1980, et al.
(författare)
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Expression of ezrin radixin moesin proteins in the adult subventricular zone and the rostral migratory stream.
- 2010
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Ingår i: Neuroscience. - : Elsevier BV. - 1873-7544 .- 0306-4522. ; 167:2, s. 312-22
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Tidskriftsartikel (refereegranskat)abstract
- Continuous proliferation occurs in the adult subventricular zone (SVZ) of the lateral ventricles throughout life. In the SVZ, progenitor cells differentiate into neuroblasts, which migrate tangentially along the rostral migratory stream (RMS) to reach their final destination in the olfactory bulb. These progenitor cells mature and integrate into the existing neural network of the olfactory bulb. Long distance migration of neuroblasts in the RMS requires a highly dynamic cytoskeleton with the ability to respond to surrounding stimuli. Radixin is a member of the ERM (Ezrin, Radixin, Moesin) family, which connect the actin cytoskeleton to the extracellular matrix through transmembrane proteins. The membrane-cytoskeleton linker proteins of the ERM family may regulate cellular events with a high demand on cytoskeleton plasticity, such as cell motility. Recently, specific expression of the ERM protein ezrin was shown in the RMS. Radixin however has not been characterized in this region. Here we used immunohistochemistry and confocal microscopy to examine the expression of radixin in the different cell types of the adult subventricular zone niche and in the RMS. Our findings indicate that radixin is strongly expressed in neuroblasts of the adult RMS and subventricular zone, and also in Olig2-positive cells. We also demonstrate the presence of radixin in the cerebral cortex, striatum, cerebellum, thalamus, hippocampus as well as the granular and periglomerular layers of the olfactory bulb. Our studies also reveal the localization of radixin in neurosphere culture studies and we reveal the specificity of our labeling using Western blotting. The expression pattern demonstrated here suggests a role for radixin in neuronal migration and differentiation in the adult RMS. Understanding how adult neuronal migration is regulated is of importance for the development of new therapeutic interventions using endogenous repair for neurodegenerative diseases.
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