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      Activating Transcription Factor 3 and the Nervous System

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          Abstract

          Activating transcription factor 3 (ATF3) belongs to the ATF/cyclic AMP responsive element binding family of transcription factors and is often described as an adaptive response gene whose activity is usually regulated by stressful stimuli. Although expressed in a number of splice variants and generally recognized as a transcriptional repressor, ATF3 has the ability to interact with a number of other transcription factors including c-Jun to form complexes which not only repress, but can also activate various genes. ATF3 expression is modulated mainly at the transcriptional level and has markedly different effects in different types of cell. The levels of ATF3 mRNA and protein are normally very low in neurons and glia but their expression is rapidly upregulated in response to injury. ATF3 expression in neurons is closely linked to their survival and the regeneration of their axons following axotomy, and that in peripheral nerves correlates with the generation of a Schwann cell phenotype that is conducive to axonal regeneration. ATF3 is also induced by Toll-like receptor (TLR) ligands but acts as a negative regulator of TLR signaling, suppressing the innate immune response which is involved in immuno-surveillance and can enhance or reduce the survival of injured neurons and promote the regeneration of their axons.

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          A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man.

          A peripheral mononeuropathy was produced in adult rats by placing loosely constrictive ligatures around the common sciatic nerve. The postoperative behavior of these rats indicated that hyperalgesia, allodynia and, possibly, spontaneous pain (or dysesthesia) were produced. Hyperalgesic responses to noxious radiant heat were evident on the second postoperative day and lasted for over 2 months. Hyperalgesic responses to chemogenic pain were also present. The presence of allodynia was inferred from the nocifensive responses evoked by standing on an innocuous, chilled metal floor or by innocuous mechanical stimulation, and by the rats' persistence in holding the hind paw in a guarded position. The presence of spontaneous pain was suggested by a suppression of appetite and by the frequent occurrence of apparently spontaneous nocifensive responses. The affected hind paw was abnormally warm or cool in about one-third of the rats. About one-half of the rats developed grossly overgrown claws on the affected side. Experiments with this animal model may advance our understanding of the neural mechanisms of neuropathic pain disorders in humans.
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            Activating transcription factor 3 (ATF3) induction by axotomy in sensory and motoneurons: A novel neuronal marker of nerve injury.

            Activating transcription factor 3 (ATF3), a member of ATF/CREB family of transcription factors, is induced in a variety of stressed tissue. ATF3 regulates transcription by binding to DNA sites as a homodimer or heterodimer with Jun proteins. The purpose of this study was to examine the expression and regulation of ATF3 after axonal injury in neurons in dorsal root ganglia (DRG) and spinal cord. In naive rats, ATF3 was not expressed in the DRG and spinal cord. Following the cut of peripheral nerve, ATF3 was immediately induced in virtually all DRG neurons and motoneurons that were axotomized, and the time course of induction was dependent on the distance between the injury site and the cell body. Double labeling using immunohistochemistry revealed that the population of DRG neurons expressing ATF3 included those expressing c-jun, and in motoneurons ATF3 and c-jun were concurrently expressed after axotomy. In contrast to c-jun, ATF3 was not induced transsynaptically in spinal dorsal horn neurons. We conclude that ATF3 is specifically induced in sensory and motoneurons in the spinal cord following nerve injury and should be regarded as an unique neuronal marker of nerve injury in the nervous system. Copyright 2000 Academic Press.
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              Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction.

              Paclitaxel chemotherapy frequently induces neuropathic pain during and often persisting after therapy. The mechanisms responsible for this pain are unknown. Using a rat model of paclitaxel-induced painful peripheral neuropathy, we have performed studies to search for peripheral nerve pathology. Paclitaxel-induced mechano-allodynia and mechano-hyperalgesia were evident after a short delay, peaked at day 27 and finally resolved on day 155. Paclitaxel- and vehicle-treated rats were perfused on days 7, 27 and 160. Portions of saphenous nerves were processed for electron microscopy. There was no evidence of paclitaxel-induced degeneration or regeneration as myelin structure was normal and the number/density of myelinated axons and C-fibres was unaltered by paclitaxel treatment at any time point. In addition, the prevalence of ATF3-positive dorsal root ganglia cells was normal in paclitaxel-treated animals. With one exception, at day 160 in myelinated axons, total microtubule densities were also unaffected by paclitaxel both in C-fibres and myelinated axons. C-fibres were significantly swollen following paclitaxel at days 7 and 27 compared to vehicle. The most striking finding was significant increases in the prevalence of atypical (swollen and vacuolated) mitochondria in both C-fibres (1.6- to 2.3-fold) and myelinated axons (2.4- to 2.6-fold) of paclitaxel-treated nerves at days 7 and 27. Comparable to the pain behaviour, these mitochondrial changes had resolved by day 160. Our data do not support a causal role for axonal degeneration or dysfunction of axonal microtubules in paclitaxel-induced pain. Instead, our data suggest that a paclitaxel-induced abnormality in axonal mitochondria of sensory nerves contributes to paclitaxel-induced pain.
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                Author and article information

                Journal
                Front Mol Neurosci
                Front. Mol. Neurosci.
                Frontiers in Molecular Neuroscience
                Frontiers Research Foundation
                1662-5099
                14 February 2012
                2012
                : 5
                : 7
                Affiliations
                [1] 1simpleMedical Education Centre, Newham University Hospital London, UK
                [2] 2simplePerinatal Brain Repair Group, Institute for Women’s Health, University College London London, UK
                [3] 3simpleResearch Department of Cell and Developmental Biology, University College London London, UK
                Author notes

                Edited by: Simone Di Giovanni, University of Tuebingen, Germany

                Reviewed by: Hiroshi Kiyama, Nagoya University, Japan; Simone Di Giovanni, University of Tuebingen, Germany

                *Correspondence: Patrick Norval Anderson, Department of Cell and Developmental Biology, Anatomy Building, University College London, Gower Street, London WC1E 6BT, UK. e-mail: p.anderson@ 123456ucl.ac.uk
                Article
                10.3389/fnmol.2012.00007
                3278981
                22347845
                a3c09722-bd5d-449d-be3e-abe72167a652
                Copyright © 2012 Hunt, Raivich and Anderson.

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.

                History
                : 06 December 2011
                : 20 January 2012
                Page count
                Figures: 3, Tables: 2, Equations: 0, References: 177, Pages: 17, Words: 16072
                Categories
                Neuroscience
                Review Article

                Neurosciences
                atf3,c-jun
                Neurosciences
                atf3, c-jun

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