<i>c-jun</i>is essential for sympathetic neuronal death induced by NGF withdrawal but not by p75 activation

Palmada, Mònica; Kanwal, S.; Rutkoski, Nancy J.; Gustafson-Brown, Cindy; Johnson, Randall S.; Wisdom, Ron; Carter, B.D.

doi:10.1083/jcb.200112129

Cited by 115 publications

(115 citation statements)

References 54 publications

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“…The level of the c-jun mRNA and c-Jun protein increases rapidly in sympathetic neurons after NGF withdrawal, and microinjection of neutralizing antibodies against c-Jun or expression of a c-Jun dominant-negative mutant protects sympathetic neurons against NGF withdrawal-induced death, 4,5 as does conditional knockout of the c-jun gene in sympathetic neurons isolated from mice with a floxed c-jun gene. 6 These observations supported the idea that NGF withdrawal-induced death involves the transcriptional induction of genes that activate the cell death programme. In addition, the observation that c-Jun N-terminal phosphorylation increases after NGF withdrawal led to the demonstration that c-Jun N-terminal kinases (JNKs) are activated in sympathetic neurons deprived of NGF and that JNK activity is required for NGF withdrawal-induced death.…”

Section: Ngf Withdrawal-induced Death Requires Transcription and Invosupporting

confidence: 59%

BH3-only proteins: key regulators of neuronal apoptosis

Ham

Towers²,

Gilley³

et al. 2005

Cell Death Differ

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The molecular mechanisms of neuronal apoptosis have been intensively studied because a considerable amount of apoptosis occurs during the normal development of the mammalian nervous system. This death is important for establishing neuronal populations of the correct size and for ensuring that neurons that contact inappropriate targets are eliminated. 1,2 A second reason for the interest in this area is that there is increasing evidence that apoptosis is one of the mechanisms of neuronal death following acute injuries to the nervous system, such as stroke or traumatic brain injury, and neurons often die by apoptosis in cell culture and animal models of chronic human neurodegenerative disorders. 2 The aim of this article is to review recent work on the function and regulation of the BH3-only subfamily of Bcl-2 proteins in neurons, with an emphasis on studies with sympathetic neurons, cerebellar granule neurons (CGNs) and motoneurons, the best studied in vitro models of neuronal apoptosis, and work that has involved the analysis of neurons from mutant mice.

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Section: Ngf Withdrawal-induced Death Requires Transcription and Invosupporting

confidence: 59%

BH3-only proteins: key regulators of neuronal apoptosis

Ham

Towers²,

Gilley³

et al. 2005

Cell Death Differ

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“…Previous studies indicate that neuronal stress can promote cell death in some contexts or axon regrowth in others (36,37). However, the control of both responses in RGCs revealed by our current work demonstrates that DLK mechanistically couples these disparate reactions at an early stage of the injury response.…”

Section: Discussionmentioning

confidence: 36%

DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury

Watkins¹,

Wang²,

Huntwork‐Rodriguez³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

283

427

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The cell intrinsic factors that determine whether a neuron regenerates or undergoes apoptosis in response to axonal injury are not well defined. Here we show that the mixed-lineage dual leucine zipper kinase (DLK) is an essential upstream mediator of both of these divergent outcomes in the same cell type. Optic nerve crush injury leads to rapid elevation of DLK protein, first in the axons of retinal ganglion cells (RGCs) and then in their cell bodies. DLK is required for the majority of gene expression changes in RGCs initiated by injury, including induction of both proapoptotic and regeneration-associated genes. Deletion of DLK in retina results in robust and sustained protection of RGCs from degeneration after optic nerve injury. Despite this improved survival, the number of axons that regrow beyond the injury site is substantially reduced, even when the tumor suppressor phosphatase and tensin homolog (PTEN) is deleted to enhance intrinsic growth potential. These findings demonstrate that these seemingly contradictory responses to injury are mechanistically coupled through a DLK-based damage detection mechanism.A xonal damage results in significant neuronal cell death and axon degeneration, often leading to permanent functional deficits. For example, optic nerve crush rapidly induces a stress response in retinal ganglion cells (RGCs) that includes profound alterations in gene expression patterns (1) and ultimately leads to apoptosis of these neurons (2). As axon injury may occur a significant distance from the cell body, it has been proposed that retrograde molecular motors play a critical role in conveying damage signals to the nucleus, allowing the cell to respond to damage (3). Attenuation of this transport mechanism has been shown to reduce degeneration, suggesting that the ability of the nucleus to detect an insult is an essential component of the injury response (4).Recent data suggest that dual leucine zipper kinase (DLK) is an essential component of the neuronal response to axon damage. DLK protein is present in axons, and protein levels are increased in response to axonal injury (5). Loss of DLK has been shown to protect distal axons from Wallerian degeneration (6) and to abrogate stress-induced retrograde c-Jun N-terminal kinase (JNK) signaling through interaction with the scaffolding protein JNK-interacting protein 3 (JIP3) (7-9). In many instances, injury-induced JNK activation in neurons results in apoptosis through phosphorylation of activator protein 1 (AP-1) transcription factors such as c-Jun, which initiates a proapoptotic gene expression program (10, 11). Consistent with this, genetic deletion of JNK2 and/or JNK3 is sufficient to protect neurons from degeneration in a range of CNS injury models, including axotomy (12-14), although the role of DLK in these contexts is not known.In contrast, DLK has been shown to regulate axon regeneration after axonal injury in adult peripheral nerves (9) and invertebrate systems (5, 15). The mechanism underlying the divergence between these apoptotic and reg...

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“…22,23 JNK activation leads to the upregulation, phosphorylation and activation of the transcription factor c-Jun which is essential for sympathetic neuronal apoptosis in response to nerve growth factor (NGF) withdrawal. 24,25 We examined whether the JNK pathway was activated in sympathetic neurons in response to ER stress by using immunohistochemistry to assess the phosphorylation state of c-Jun. Although untreated neurons showed virtually no phospho-c-Jun staining, by 18 h neurons treated with TU showed high levels of nuclear localized phosphorylated To determine if the MLK-mediated JNK pathway was required for ER stress-induced apoptosis, we treated sympathetic neurons with TU in the presence of a MLK inhibitor, CEP-11004.…”

Section: Resultsmentioning

confidence: 99%

“…JNK signaling is important in other models of neuronal apoptosis as well. 20,25,33 For example, during NGF deprivation-induced apoptosis, JNK signaling appears to be important for the transcriptional upregulation of BH3-only proteins DP5/Harakiri and Bim. 4 We found DP5 and Puma levels were induced, however, Bim and Noxa levels did not change significantly after TU treatment in neurons (Figure 3a and b).…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic reticulum stress-induced apoptosis requires bax for commitment and Apaf-1 for execution in primary neurons

Smith

Deshmukh

2007

Cell Death Differ

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Apoptosis triggered by endoplasmic reticulum (ER) stress is associated with various pathophysiological conditions including neurodegenerative diseases and ischemia. However, the mechanism by which ER stress induces neuronal apoptosis remains controversial. Here we identify the pathway of apoptosis carried out in sympathetic neurons triggered to die by ER stressinducing agent tunicamycin. We find that ER stress induces a neuronal apoptotic pathway which upregulates BH3-only genes DP5 and Puma. Importantly, we show that ER stress commits neurons to die before cytochrome c release and this commitment requires Bax activation and c-jun N-terminal kinase signaling. Furthermore, ER stress engages the mitochondrial pathway of death as neurons release cytochrome c and Apaf-1 deficiency is sufficient to block apoptosis. Our findings identify a critical function of Bax in committing neurons to ER stress-induced apoptosis and clarify the importance of the apoptosome as the non-redundant caspase activation pathway to execute neuronal apoptosis in response to ER stress.

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c-junis essential for sympathetic neuronal death induced by NGF withdrawal but not by p75 activation

Cited by 115 publications

References 54 publications

BH3-only proteins: key regulators of neuronal apoptosis

BH3-only proteins: key regulators of neuronal apoptosis

DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury

Endoplasmic reticulum stress-induced apoptosis requires bax for commitment and Apaf-1 for execution in primary neurons

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