Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Axonal lesions to the optic nerve (ON) induce c-Jun expression in retinal ganglion cells (RGCs) of the rat in vivo. Detailed investigations using retrograde tracers, and double labeling studies for c-Jun and regeneration-associated factors, such as the growth-associated protein GAP-43, have suggested that this upregulation of c-Jun is part of a cell body response in an abortive attempt of affected RGCs to survive and regenerate an axon. On the other hand, prolonged expression of c-Jun protein has in several paradigms of neurodegeneration been linked to the induction of apoptotic cell death. In the present study, we examined the time course and subcellular localization of c-Jun protein by immunocytochemistry on retinal sections after optic nerve crush and carried out double labeling for c-Jun protein and DNA strand breaks to detect apoptosis on the same sections. Several days after ON lesion, a subpopulation of RGCs was detected in which c-Jun protein was not confined to the nucleus, but also located in the cytoplasm. In addition, RGCs were seen that displayed morphological signs of apoptosis, DNA strand breaks, and c-Jun immunoreactivity at the same time. Therefore, c-Jun expression is not confined to intact or regenerating ganglion cells, but also occurs in cells that are destined to die. Our results suggest that the decision to undergo either fate depends on additional signaling events that modulate the transcriptional actions of c-Jun.
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PMID:Expression of c-Jun protein in degenerating retinal ganglion cells after optic nerve lesion in the rat. 929

Adult olivocerebellar axons are capable of vigorous regeneration when provided with growth-permissive environmental conditions. To elucidate the contribution of intrinsic properties to the regenerative capabilities of inferior olivary neurons, we have examined the cellular modifications occurring in these neurons following axotomy and target deprivation in the absence of exogenous growth-promoting influences. Axotomized inferior olivary neurons undergo perikaryal shrinkage, dendritic atrophy and a loss of anti-calbindin immunoreactivity. A conspicuous cell death occurs during the first few weeks after lesion, but about 35% of the affected neurons survive up to 60 days. Coincidentally, a subset of the injured nerve cells become strongly reactive for NADPH diaphorase histochemistry, and this expression is correlated with survival in the medial accessory olive and in the principal olive. In addition, the affected neurons express or maintain the expression of several markers related to regenerative processes, including transcription factors c-Jun, JunD and Krox-24, the growth-associated protein GAP-43 and the developmentally regulated calcitonin gene-related peptide (CGRP). The expression of all these markers is sustained up to two months after lesion, the longest survival time examined. These results show that although adult axotomized inferior olivary neurons undergo severe regressive modifications leading to a conspicuous cell loss, at least a subset of them is resistant to the lesion. In addition, the long-lasting expression of several axon-growth associated markers expressed in these neurons in response to injury reveals that they are endowed with a strong intrinsic regenerative potential.
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PMID:Degenerative phenomena and reactive modifications of the adult rat inferior olivary neurons following axotomy and disconnection from their targets. 962 55

Axon regeneration requires that injured neurons reinitiate long-distance growth and upregulate specific genes. To address the question of whether inhibitory environmental cues along the axon could exert a negative, tonic downregulation of growth-associated genes, we have examined adult rat Purkinje cells, which are endowed with poor regenerative capabilities. First we have compared their response to axotomy with that of neurons of the inferior olive, lateral reticular nucleus, and deep cerebellar nuclei, all of which vigorously regenerate into growth-permissive transplants. These injured neurons upregulate the transcription factors c-Jun and JunD, GAP-43, and NADPH diaphorase. In contrast, most axotomized Purkinje cells fail to express any of these markers, showing that the strength of this response parallels the regenerative potential of the examined neuron populations. However, strong upregulation of the same genes can be induced in Purkinje cells after colchicine injection into the uninjured adult cerebellum, indicating that their expression could be controlled by retrograde signals. To assess whether myelin-associated neurite growth inhibitory proteins contribute to this regulation, we applied the neutralizing antibodies IN-1 against one of the main inhibitory components of central myelin (NI-250) either in vivo or in vitro to organotypic cerebellar cultures. Application of IN-1 antibodies induces the upregulation of c-Jun, JunD, and NADPH diaphorase in Purkinje cells, showing that their expression is suppressed constitutively by myelin-associated neurite growth inhibitors. Thus, the inhibitory activity of the IN-1 antigen on axon growth is not restricted to the control of growth cone motility but also involves a retrograde regulation of gene expression in adult central neurons.
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PMID:Retrograde regulation of growth-associated gene expression in adult rat Purkinje cells by myelin-associated neurite growth inhibitory proteins. 974 59

The superior olivary complex (SOC) is part of the auditory brainstem of the vertebrate brain. Residing ventrally in the rhombencephalon, it receives sensory signals from both cochleae through multisynaptic pathways. Neurons of the SOC are also a target of bilateral descending projections. Ascending and descending efferents of the SOC affect the processing of auditory signals on both sides of the brainstem and in both organs of Corti. The pattern of connectivity indicates that the SOC fulfills functions of binaural signal integration serving sound localization. But whereas many of these connectional features are shared with the inferior colliculus (with the important exception of a projection to the inner ear), cellular and molecular investigations have shown that cells residing in SOC are unique in several respects. Unlike those of other auditory brainstem nuclei, they specifically express molecules known to be involved in development, plasticity, and learning (e.g., GAP-43 mRNA, specific subunits of integrin). Moreover, neurons of the SOC in adult mammals respond to various kinds of hearing impairment with the expression of plasticity-related substances (e.g., GAP-43, c-Jun, c-Fos, cytoskeletal elements), indicative of a restructuring of auditory connectivity. These observations suggest that the SOC is pivotal in the developmental and adaptive tuning of binaural processing in young and adult vertebrates.
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PMID:Plasticity of the superior olivary complex. 1107 20

Over the past few years we have studied the plasticity of the adult auditory brainstem in the rat following unilateral changes to the pattern of sensory activation, either by intracochlear electrical stimulation or by deafening. We discovered that modifications to afferent activity induced changes in the molecular composition and cellular morphology throughout the auditory brainstem, including its major centers: the cochlear nucleus complex, the superior olivary complex, and the inferior colliculus. The time window studied ranged from 2 h to over 1 year following induction of changes to afferent activity. The molecular markers employed include the NMDA receptor subunit type 1, the cAMP response element binding protein (CREB), the immediate early gene products c-Fos, c-Jun and Egr-1, the growth and plasticity-associated protein GAP-43 and its mRNA, the calcium binding protein calbindin, the cell adhesion molecule integrin-alpha(1), the microtubule-associated protein MAP-1b, and the neurofilament light chain (NF-L). As a consequence of the specific electrical stimulation of the auditory afferents or the loss of hearing, a cascade of events is triggered that apparently modifies the integrative action and computational abilities of the central auditory system. An attempt is made to relate the diverse phenomena observed to a common molecular signaling network that is suspected to bridge sensory experience to changes in the structure and function of the brain. Eventually, a thorough understanding of these events will be essential for the specific diagnosis of patients, optimal timing for implantation, and suitable parameters for running of a cochlear implant or an auditory brainstem implant in humans. In this report an overview of the results obtained in the past years in our lab is presented, flanked by an introduction into the history of plasticity research and a model proposed for intracellular signal cascades related to activity-dependent plasticity.
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PMID:Activity-dependent plasticity in the adult auditory brainstem. 1184 62

Long-distance axon regeneration requires the activation of a specific set of neuronal growth-associated genes. Adult Purkinje cells fail to upregulate these molecules in response to axotomy and show extremely weak regenerative properties. Nevertheless, starting from several months after injury, transected Purkinje axons undergo spontaneous sprouting. Here, we asked whether long-term injured Purkinje cells acquire novel intrinsic growth properties that enable them to upregulate growth-associated genes and sustain axon regeneration. To test this hypothesis, we examined axon growth and cell body changes in adult rat Purkinje neurons following axotomy and implantation of embryonic neocortical tissue or Schwann cells into the injury track. Purkinje cells that survived over 6 months after injury/transplantation displayed profuse sprouting in the injured cerebellum and developed extensive networks of terminal branches into embryonic neocortical grafts. In addition, severed Purkinje axons exposed to these transplants 6 months after injury grew faster than their counterparts confronted with the same environment immediately after axotomy. Nevertheless, long-term injured Purkinje cells failed to regenerate stem neurites into Schwann cell grafts, and, under all experimental conditions, they did not upregulate growth-associated molecules, including c-Jun, GAP-43, SNAP-25, and NADPH-diaphorase. These results indicate that the long-term injured Purkinje cells remain unable to activate the gene program required to sustain axon regeneration and their plasticity is restricted to terminal arbor remodeling. We propose that the delayed growth of injured Purkinje cells reflects an adaptive phenomenon by which the severed axon stump develops a new terminal arbor searching for alternative connections with local partners.
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PMID:Long-term injured purkinje cells are competent for terminal arbor growth, but remain unable to sustain stem axon regeneration. 1209 80

Permanent or temporary disruption of cerebral blood flow rapidly depletes brain regions of their limited energy reserves (glycogen, glucose, oxygen, ATP) leading to an energy crisis. Tissue damage occurs due to the energy crisis. The central part of the damage, the ischaemic "core" region is surrounded by zones of the shell-like penumbra. Necrotic, as well as apoptotic cell death could be identified in the penumbra. Going away from the ischaemic core different neurochemical processes are occurring by space and time. "Immediate early response" genes (c-fos, fos-B, c-Jun, krox 20, 24) are activated, heatshock proteins (hsp 70, 72, HSF, HSE, HIF), cytokines (TNF-alpha, IL-1 beta), inflammatory factors (COX), adhesion and glial factors (ICAM-1, ELAM-1, P-selectin), vasoactive factors (IL-6, -10, PAF), reactive oxigen radicals and connected factors (O2, OH, NO, NOS, SOD) are produced within minutes and hours. Cell deaths, necrosis and apoptosis due to the activation of calpains, caspases and nucleases occur in days. In parallel, growth factors and plasticity proteins (BDNF, NGF, TGF-beta, VEGF, PDGF, GAP-43) are activated as a basis of functional rehabilitation.
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PMID:[Regulatory mechanisms in focal cerebral ischemia. New possibilities in neuroprotective therapy]. 1212 84

Following axotomy, cerebellar Purkinje cells (PCs) do not elongate their axons, even in a favourable environment, and are resistant to death. They have no constitutive presence of common growth-associated proteins, such as GAP-43 and c-Jun. Previous experiments show that injured transgenic PCs overexpressing GAP-43 exhibit a profuse sprouting along the axon and at its severed end. Nevertheless, the lesioned axons are unable to regenerate either spontaneously or into growth-permissive environments. In addition, a considerable number of GAP-43 transgenic PCs degenerate after injury. c-Jun is an inducible transcription factor expressed in axotomized central neurons and regenerating peripheral neurons. It also contributes to programmed cell death during development. To test whether c-Jun could modify the response of PCs to axotomy or enhance the growth/death phenomena of GAP-43 Purkinje neurons, we generated transgenic mice overexpressing c-Jun in PCs. However, c-Jun upregulation did not affect the adult intact phenotype of these neurons and their regenerative and survival capabilities after axotomy. Also in the cross-bred GAP-43/c-Jun mice, c-Jun did not modify the response of GAP-43 PCs to axotomy. By contrast, in organotypic cultures of cerebellum taken from 9-day-old-pups, the survival capabilities of PCs overexpressing c-Jun decreased, in association with a consistent c-Jun phosphorylation. On the whole our data show that c-Jun alone is unable to trigger regenerative or degenerative phenomena in PCs and suggest that the cellular action of this early gene in developing and mature neurons strongly depends on interplaying intracellular signals.
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PMID:Regenerative and survival capabilities of Purkinje cells overexpressing c-Jun. 1215 35

The expression of early response gene proteins c-Fos, c-Jun, and GAP-43 and their association with 6-hydroxydopamine (6-OHDA)-mediated oxidative injury were investigated using catecholaminergic PC12 cell line. Significant induction in the expression of c-Fos (P < 0.01), c-Jun (P < 0.001) and GAP-43 (P < 0.05) was observed following 2 h exposure to 6-OHDA (10(-6) M), which persisted during 24 h of observation. The exposed cells exhibited an increase in lipid peroxidation (48, 59 and 33%) along with decreased catalase activity (49, 30 and 13%) and glutathione levels (39, 28 and 16%) following 24, 48 and 72 h exposure, respectively. A concentration-dependent functional impairment of mitochondria as studied by 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and decreased cell survival were also observed following 6-OHDA (10(-4), 10(-5) M) exposure for 24, 48 and 72 h. The results indicate a role of the early response gene in oxidative stress-mediated dopaminergic cell death by 6-OHDA. Similar mechanisms may also be operative in the development of Parkinson's disease, as an increased presence/formation of endogenous 6-OHDA has been reported in Parkinson's patients.
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PMID:Induced expression of early response genes/oxidative injury in rat pheochromocytoma (PC12) cell line by 6-hydroxydopamine: implication for Parkinson's disease. 1221 41

Although adult mammalian neurons are able to regenerate their axons in the peripheral nervous system under certain conditions, they are not able to do it in the central nervous system. The environment surrounding the severed axons appears to be a key factor for axon regeneration. Many studies aiming to enhance axon regeneration in the CNS of adult mammals have successfully manipulated this environment by adding growth permissive molecules and/or neutralizing growth inhibitory molecules. In both cases, the number of axons able to regenerate was low and the different neuronal populations were not equal in their regenerative response, suggesting that manipulation of the environment is not always sufficient. This is particularly well illustrated in the cerebellar system, in which axotomized inferior olivary neurons regenerate when confronted with a permissive environment, whereas mature Purkinje cells do not. The intrinsic ability of a neuron to regenerate its axon is generally correlated with the intensity of its reaction to axotomy (expression of molecules, probability to die). Furthermore, molecules such as GAP-43 (growth-associated molecule) and c-Jun are involved in both axon regeneration and cell death suggesting that these two processes are linked. Surprisingly, Purkinje cells lose their capacity to regenerate their axon (even in the absence of myelin) during development before losing their capacity to react to an axotomy by cell death. These results emphasize the different reactions to axotomy between neuron types and underline that in Purkinje cells, the two cell decisions (axon regeneration and cell death) are differently regulated and therefore not part of the same signaling pathway.
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PMID:Cell death and axon regeneration of Purkinje cells after axotomy: challenges of classical hypotheses of axon regeneration. 1611 58


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