关键词： ACTIVATING TRANSCRIPTION FACTOR-3   C-JUN   SCIATIC-NERVE   AXONAL REGENERATION   GENE-EXPRESSION   SCHWANN-CELLS   OPTIC-NERVE   ADULT-RAT   INJURY   AXOTOMY  

摘要： Background: Many changes in gene expression occur in distal stumps of injured nerves but the transcriptional control of these events is poorly understood. We have examined the expression of the transcription factors ATF3 and c-Jun by non-neuronal cells during Wallerian degeneration following injury to sciatic nerves, dorsal roots and optic nerves of rats and mice, using immunohistochemistry and in situ hybridization. Results: Following sciatic nerve injury-transection or transection and reanastomosis-ATF3 was strongly upregulated by endoneurial, but not perineurial cells, of the distal stumps of the nerves by 1 day post operation (dpo) and remained strongly expressed in the endoneurium at 30 dpo when axonal regeneration was prevented. Most ATF3+ cells were immunoreactive for the Schwann cell marker, S100. When the nerve was transected and reanastomosed, allowing regeneration of axons, most ATF3 expression had been downregulated by 30 dpo. ATF3 expression was weaker in the proximal stumps of the injured nerves than in the distal stumps and present in fewer cells at all times after injury. ATF3 was upregulated by endoneurial cells in the distal stumps of injured neonatal rat sciatic nerves, but more weakly than in adult animals. ATF3 expression in transected sciatic nerves of mice was similar to that in rats. Following dorsal root injury in adult rats, ATF3 was upregulated in the part of the root between the lesion and the spinal cord (containing Schwann cells), beginning at 1 dpo, but not in the dorsal root entry zone or in the degenerating dorsal column of the spinal cord. Following optic nerve crush in adult rats, ATF3 was found in some cells at the injury site and small numbers of cells within the optic nerve displayed weak immunoreactivity. The pattern of expression of c-Jun in all types of nerve injury was similar to that of ATF3. Conclusion: These findings raise the possibility that ATF3/c-Jun heterodimers may play a role in regulating changes in gene expressio

关键词： CGRP   lumbar   P2X3   rat   sciatic   PRIMARY SENSORY NEURONS   GROWTH-FACTOR   NEUROTROPHIC FACTOR   SCIATIC-NERVE   MESSENGER-RNA   C-JUN   GENE-EXPRESSION   NEUROPEPTIDE EXPRESSION   DIFFERENTIAL REGULATION   RECEPTOR COMPONENTS  

摘要： Activating transcription factor-3 (ATF3) is a member of the ATF/CREB transcription factor superfamily and is induced in dorsal root ganglion (DRG) cells after nerve injury In order to study the regulation of ATF3, we have examined the effect of nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF) on ATF3 expression. In untreated rats, sciatic nerve transection induced ATF3 immunoreactivity in 82% of L4 DRG cells at 14 days after axotomy Intrathecal delivery of NGF or GDNF for 2 weeks commencing immediately after injury reduced the ATF3 expression to 35 and 23% of DRG cells, respectively Cell size analysis indicated that NGF had protected a population of mainly small- to medium-sized cells, but that the GDNF had protected a population of both small and large cells. This effect was confirmed by double labelling for P2X(3), CGRP and 200 kDa neurofilament, markers for small peptide-poor cells, peptide-rich cells and large cells, respectively Thus GDNF reduced the percentage of ATF3-immunoreactive P2X(3) cells from 70 to 4%, and the percentage of ATF3-immunoreactive neurofilament cells from 63 to 24%. NGF was less effective than GDNF in reducing ATF3 expression in these cell types, but reduced the percentage of ATF3-immunoreactive CGRP cells from 10% to < 1 %. These results show that ATF3 expression in specific populations of DRG cells can be modulated by exogenous supplementation of specific trophic factors, and suggest that ATF3 expression may normally be induced by the loss of target-derived NGF and GDNF.

关键词： TUMOR-NECROSIS-FACTOR   JUN NH2-TERMINAL KINASE   NF-KAPPA-B   ACTIVATED PROTEIN-KINASES   C-JUN   TRANSCRIPTION FACTOR   SIGNAL-TRANSDUCTION   GENE-EXPRESSION   MESSENGER-RNA   INDUCED APOPTOSIS  

摘要： ATF3 (Activating transcription factor 3), a member of the CREB/ATF family, can be induced by stress and growth factors in mammalian cells, and is thought to play an important role in the cardiovascular system. However, little is currently known about how the induction of ATF3 is regulated, except that the JNK pathway is involved. Here, we investigated the differential roles of the MAPK pathways involved in TNFalpha (tumour necrosis factor alpha)-induced ATF3 expression in vascular endothelial cells. In human umbilical vein endothelial cells, the expression of constitutively active MKK7 (MAPK kinase 7) increased the number of ATF3-positive cells, and dominant negative MKK7 suppressed the TNFalpha-induced expression of ATF3, indicating a requirement for the JNK pathway. In contrast, the expression of constitutively active or dominant negative MEK1/2 (MAPK/ERK kinase 1/2) suppressed or enhanced TNFalpha-mediated induction of ATF3, respectively. In support of this, the MEK1/2 specific inhibitor U0126 enhanced the expression of ATF3 induced by TNFalpha. Furthermore, the ERK pathway inhibits the TNFalpha-mediated induction of ATF3 mRNA, but not its stability, suggesting the involvement of ERK activity in the transcriptional regulation of the ATF3 gene. Our results suggest that TNFalpha-induced ATF3 gene expression is bidirectionally regulated by the JNK and ERK pathways in vascular endothelial cells.

关键词： c-jun   ATF3   axonal regeneration   neurite   PC12   neuro-2a   ACTIVATING TRANSCRIPTION FACTOR-3   PROTEINS FOLLOWING AXOTOMY   NERVE GROWTH-FACTOR   PC12 CELLS   NEURONAL DIFFERENTIATION   ENDOTHELIAL-CELLS   INDUCED APOPTOSIS   AXONAL-TRANSPORT   RESPONSE ELEMENT   DNA-BINDING  

摘要： The AP-1 transcription factor c-Jun is induced in axotomized neurons of the peripheral and central nervous systems, and in both cases upregulation of c-Jun expression has been correlated with axonal regeneration. More recently there has been interest in the c-Jun-related bZIP transcription factor, ATF3, and its function in neurons. ATF3 is also induced in nerve cells in response to axotomy and there is a correlation between increased ATF3 expression and upregulation of c-Jun in surviving neurons. Moreover, c-Jun is able to induce expression of ATF3. We investigated the effect of co-expressing c-Jun and ATF3 in two neuronal-like cell lines to model transcriptional events occurring in axotomized neurons undergoing regeneration. We show that expression of ATF3 with c-Jun significantly enhances c-Jun-mediated neurite sprouting, and that this phenotype is most likely mediated by a physical association of these two transcription factors. Our results suggest that a program of axonal regeneration is initiated when both c-Jun and ATF3 are upregulated in neurons in response to axotomy. (C) 2003 Elsevier B.V. All rights reserved.

关键词： ATF3   UVA   c-fos   immediate-early gene   DNA microarray   NF-KAPPA-B   C-JUN   ACTIVATING TRANSCRIPTION   ULTRAVIOLET-RADIATION   INDUCED EXPRESSION   ENDOTHELIAL-CELLS   SINGLET OXYGEN   REPRESSOR ATF3   GROWTH-FACTOR   GENE  

摘要： Long-wavelength UV light (UVA) is known to induce transcription of various genes in the cell and to cause a variety of pathological or protective responses in the skin. To find additional UVA-responsive genes, human skin-derived fibroblasts were exposed to UVA under non- or partially lethal conditions, and the effects of UVA on the transcriptional profile were examined by using DNA microarray and RT-PCR. Transcription of several genes including those already known to be UVA-responsive was induced to a significant extent under 50% lethal conditions of exposure. Among those, ATF3 was the most sensitive and its transcription was increased 10-fold within 1 h. Even at a non-lethal dose of UVA (8 J/cm(2)), it was increased 8-fold, if cells were cultured for 3 h post-exposure. Typical immediate-early genes such as c-fos and c-jun were not affected at this dose. We thus suggest that ATF3 could be a key regulator for a variety of cellular responses in the skin, particularly to low doses of UVA. (C) 2003 Elsevier Inc. All rights reserved.

关键词： sensory ganglia   primary culture   nerve growth factor   nerve injury   GENE-EXPRESSION   INDUCED APOPTOSIS   NERVE INJURY   ATF3   FAMILY   PROTEINS  

摘要： Activating transcription factor 3 (ATF3) has been used in as a marker of nerve injury in primary sensory neurons. The purpose of the present studies was to determine whether primary sensory ganglia in culture express ATF3 and, thus, an injured phenotype. At all time points post-plating (1 h-14 days), neurons in culture expressed ATF3 compared to undetectable expression in native ganglia. In addition, NGF was unable to rescue this injured phenotype. Thus, sensory neurons in culture represent a potential model of injured neurons. (C) 2003 Elsevier B.V. All rights reserved.

关键词： ATF3   axotomy   CAP-23   CHL1   c-jun   corticospinal   GAP-43   injury   krox-24   L1   rat   SCG10   PERIPHERAL-NERVE GRAFTS   RETINAL GANGLION-CELLS   ACTIVATING TRANSCRIPTION FACTOR-3   IMMEDIATE-EARLY GENE   ADULT-RAT   C-JUN   AXONAL REGENERATION   FUNCTIONAL RECOVERY   CORTICAL-NEURONS   CNS NEURONS  

摘要： The failure of some CNS neurons to up-regulate growth-associated genes following axotomy may contribute to their failure to regenerate axons. We have studied gene expression in rat corticospinal neurons following either proximal (intracortical) or distal (spinal) axotomy. Corticospinal neurons were retrogradely labelled with cholera toxin subunit B prior to intracortical lesions or concomitantly with spinal lesions. Alternate sections of forebrain were immunoreacted for cholera toxin subunit B or processed for mRNA in situ hybridization for ATF3, c jun, GAP-43, CAP-23, SCG10, L1, CHL1 or krox-24, each of which has been associated with axotomy or axon regeneration in other neurons. Seven days after intracortical axotomy, ATF3, c jun, GAP-43, SCG10, L1 and CHL1, but not CAP-23 or krox-24, were up-regulated by layer V pyramidal neurons, including identified corticospinal neurons. The maximum distance between the lesion and the neuronal cell bodies that up-regulated genes varied between 300 and 500 mum. However, distal axotomy failed to elicit changes in gene expression in corticospinal neurons. No change in expression of any molecule was seen in the neocortex 1 or 7 days after corticospinal axotomy in the cervical spinal cord. The expression of GAP-43, CAP-23, L1, CHL1 and SCG10 was confirmed to be unaltered after this type of injury in identified retrogradely labelled corticospinal neurons. Thus, while corticospinal neuronal cell bodies fail to respond to spinal axotomy, these cells behave like regeneration-competent neurons, up-regulating a wide range of growth-associated molecules if axotomized within the cerebral cortex.