Activating Transcription Factor 3 (ATF3) Induction by Axotomy in Sensory and Motoneurons: A Novel Neuronal Marker of Nerve Injury

Tsujino, Hiroaki; Kondo, Eiji; Fukuoka, Tetsuo; Dai, Yi; Tokunaga, Atsushi; Miki, Kenji; Yonenobu, Kazuo; Ochi, Takahiro; Noguchi, Koichi

doi:10.1006/mcne.1999.0814

Cited by 686 publications

(668 citation statements)

References 35 publications

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“…The up-regulation of ATF3 in DRG neurons was first noted at day 1 following the initial intravenous infusion and this increased expression was still present at day 10 post-infusion (the latest time point examined). Previous studies have shown that ATF3 is induced by stress stimuli and cellular damage and may have a survival/ regenerative function in sensory neurons (Seijffers et al, 2006) Following axotomy of sensory nerve fibers within the sciatic nerve (Tsujino et al, 2000), spinal nerves (Wang et al, 2003), or distal branches of the sciatic nerve (Tsuzuki et al, 2001) in the rat, ATF3 is up-regulated in neuronal cell bodies within 24 hours and this de novo expression can be maintained for weeks (Tsujino et al, 2000;Tsuzuki et al, 2001;Shortland et al, 2006). Upregulation of ATF3 in the DRG of axotomized nerves is prevented by the exogenous administration of nerve growth factor (Averill et al, 2004) and glial cell derived nerve growth factor (Wang et al, 2003).…”

Section: Impact Of Intravenous Paclitaxel On Sensory Neurons In the Drgmentioning

confidence: 99%

An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat

et al. 2007

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Paclitaxel (Taxol®) is a frontline antineoplastic agent used to treat a variety of solid tumors including breast, ovarian, or lung cancer. The major dose limiting side effect of paclitaxel is a peripheral sensory neuropathy that can last days to a lifetime. To begin to understand the cellular events that contribute to this neuropathy, we examined a marker of cell injury/regeneration (activating transcription factor 3; ATF3), macrophage hyperplasia/hypertrophy; satellite cell hypertrophy in the dorsal root ganglion (DRG) and sciatic nerve as well as astrocyte and microglial activation within the spinal cord at 1, 4, 6 and 10 days following intravenous infusion of therapeutically relevant doses of paclitaxel. At day 1 post-infusion there was an up-regulation of ATF3 in a subpopulation of large and small DRG neurons and this up-regulation was present through day 10. In contrast, hypertrophy of DRG satellite cells, hypertrophy and hyperplasia of CD68+ macrophages in the DRG and sciatic nerve, ATF3 expression in S100β+ Schwann cells and increased expression of the microglial marker (CD11b) and the astrocyte marker glial fibrillary acidic protein in the spinal cord were not observed until day 6 post infusion. The present results demonstrate that using the time points and markers examined, DRG neurons show the first sign of injury which is followed days later by other neuropathological changes in the DRG, peripheral nerve and dorsal horn of the spinal cord. Understanding the cellular changes that generate and maintain this neuropathy may allow the development of mechanism-based therapies to attenuate or block this frequently painful and debilitating condition.

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Section: Impact Of Intravenous Paclitaxel On Sensory Neurons In the Drgmentioning

confidence: 99%

An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat

et al. 2007

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“…While ATF3 was proposed as a marker for injured neurons (Tsujino et al, 2000), it also can be induced in glial cells. This was first reported by Hunt et al (2004) in Schwann cells in the sciatic nerve distal to a lesion.…”

Section: Discussionmentioning

confidence: 99%

“…Heterodimerization of ATF3 with members of the Jun family have been emphasized (e.g., Hai and Curran, 1991;Tsujino et al, 2000;Nakagomi et al, 2003). In addition to increasing ATF3, axotomy increases immunoreactivity to c-Jun, Jun B and Jun D in the SCG.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, we have recently found that, while ATF3 is not normally expressed in sympathetic neurons in the superior cervical ganglion (SCG), it is expressed in these neurons after transection of the postganglionic internal and external carotid nerves (Boeshore et al, 2004;Hyatt-Sachs, Schreiber, Shoemaker, Sabe, Reed, and Zigmond submitted). While ATF3 has been proposed as a marker for injured neurons (Tsujino et al, 2000), in a study on the corticospinal tract after axotomy, Mason et al (2003) found that the expression of ATF3 increased following a proximal lesion (i.e., a lesion 350-500 μm from the cell soma), but not following a more distal lesion.…”

Section: Introductionmentioning

confidence: 99%

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Activating transcription factor 3 immunoreactivity identifies small populations of axotomized neurons in rat cervical sympathetic ganglia after transection of the preganglionic cervical sympathetic trunk

Zigmond

Vaccariello

2007

Brain Research

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Activating transcription factor 3 (ATF3) has been proposed as a marker for injured neurons. Thus, while undetectable normally in sensory, motor, or sympathetic neurons, ATF3--like immunoreactivity (ATF3-IR) is readily detectable in such cells after axotomy. Here we examined ATF3-IR in the superior cervical ganglion (SCG) and the middle and inferior cervical ganglia (MICG) after transection of the predominantly preganglionic cervical sympathetic trunk (CST). The purpose of the study was to determine whether neurons in the SCG would exhibit ATF3-IR after decentralization and, if they did not, whether the induction of ATF3-IR was sensitive enough to identify the small numbers of neurons in the SCG and MICG that project their axons into the CST. Following transection of the CST, the majority of deafferented neurons in the SCG showed no ATF3-IR; however, a small group of neurons in both the SCG and MICG were labeled, and the location of the labeled neurons within these ganglia corresponded to that of neurons axotomized by this procedure. Furthermore, the ATF3-positive neurons in the MICG could be retrogradely labeled from the transected CST. In addition, a large number of smaller cells were labeled in the SCG, though not in the MICG, and some of these cells were double labeled with an antiserum to the glial protein S100. These data indicate that, after transection of the CST, neuronal labeling in the SCG and MICG is restricted to axotomized neurons but that in addition there is extensive labeling of glial cells associated with anterograde degeneration within the SCG.

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“…It is known that ATF-3 regulates gene expression through dimerizing or interacting with other transcription factors in the leucine zipper family like Fos/Jun [35,36], which allows binding to Ap1 and CRE/ATF promoters [37,38]. Upon injury, ATF-3 is upregulated in many neurons in the CNS [39,40] and peripheral nervous system [41,42]. Upon overexpression, ATF-3 stimulates enhanced neurite outgrowth in vitro, suggesting that the transcription factor increases growth plasticity in neurons, although the exact transcriptional mechanism remains unclear.…”

Section: Transcription Factor Involvement In Dendritic Plasticitymentioning

confidence: 99%

Transcriptional and Epigenetic Regulation in Injury-Mediated Neuronal Dendritic Plasticity

Wang

et al. 2016

Neurosci. Bull.

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Injury to the nervous system induces localized damage in neural structures and neuronal death through the primary insult, as well as delayed atrophy and impaired plasticity of the delicate dendritic fields necessary for interneuronal communication. Excitotoxicity and other secondary biochemical events contribute to morphological changes in neurons following injury. Evidence suggests that various transcription factors are involved in the dendritic response to injury and potential therapies. Transcription factors play critical roles in the intracellular regulation of neuronal morphological plasticity and dendritic growth and patterning. Mounting evidence supports a crucial role for epigenetic modifications via histone deacetylases, histone acetyltransferases, and DNA methyltransferases that modify gene expression in neuronal injury and repair processes. Gene regulation through epigenetic modification is of great interest in neurotrauma research, and an early picture is beginning to emerge concerning how injury triggers intracellular events that modulate such responses. This review provides an overview of injury-mediated influences on transcriptional regulation through epigenetic modification, the intracellular processes involved in the morphological consequences of such changes, and potential approaches to the therapeutic manipulation of neuronal epigenetics for regulating gene expression to facilitate growth and signaling through dendritic arborization following injury.

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Activating Transcription Factor 3 (ATF3) Induction by Axotomy in Sensory and Motoneurons: A Novel Neuronal Marker of Nerve Injury

Cited by 686 publications

References 35 publications

An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat

An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat

Activating transcription factor 3 immunoreactivity identifies small populations of axotomized neurons in rat cervical sympathetic ganglia after transection of the preganglionic cervical sympathetic trunk

Transcriptional and Epigenetic Regulation in Injury-Mediated Neuronal Dendritic Plasticity

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