Deafferentation-Induced Activation of NFAT (Nuclear Factor of Activated T-Cells) in Cochlear Nucleus Neurons during a Developmental Critical Period: A Role for NFATc4-Dependent Apoptosis in the CNS

Luoma, Jessie I.; Zirpel, Lance

doi:10.1523/jneurosci.5227-07.2008

Cited by 50 publications

(38 citation statements)

References 55 publications

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“…Furthermore, deafferentiation-induced neuronal loss in the cochlear nucleus has also recently been proposed to be mediated not only by NFATc4 activation but also by subsequent FasL-mediated apoptosis (64), thus mirroring our mechanistic findings concerning lithiuminduced apoptosis. It should be noted, however, that apart from the NFAT/Fas-mediated mechanism described here, a distinct and compatible mechanism by which GSK-3 inhibition facilitates apoptosis through the extrinsic pathway has been recently reported.…”

Section: Discussionsupporting

confidence: 86%

NFAT/Fas signaling mediates the neuronal apoptosis and motor side effects of GSK-3 inhibition in a mouse model of lithium therapy

Gómez‐Sintes¹,

Lucas²

2010

J. Clin. Invest.

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Use of lithium, the mainstay for treatment of bipolar disorder, is limited by its frequent neurological side effects and its risk for overdose-induced toxicity. Recently, lithium has also been proposed as a treatment for Alzheimer disease and other neurodegenerative conditions, but clinical trials have been hampered by its prominent side effects in the elderly. The mechanisms underlying both the positive and negative effects of lithium are not fully known. Lithium inhibits glycogen synthase kinase-3 (GSK-3) in vivo, and we recently reported neuronal apoptosis and motor deficits in dominant-negative GSK-3-transgenic mice. We hypothesized that therapeutic levels of lithium could also induce neuronal loss through GSK-3 inhibition. Here we report induction of neuronal apoptosis in various brain regions and the presence of motor deficits in mice treated chronically with lithium. We found that GSK-3 inhibition increased translocation of nuclear factor of activated T cells c3/4 (NFATc3/4) transcription factors to the nucleus, leading to increased Fas ligand (FasL) levels and Fas activation. Lithium-induced apoptosis and motor deficits were absent when NFAT nuclear translocation was prevented by cyclosporin A administration and in Fas-deficient lpr mice. The results of these studies suggest a mechanism for lithium-induced neuronal and motor toxicity. These findings may enable the development of combined therapies that diminish the toxicities of lithium and possibly other GSK-3 inhibitors and extend their potential to the treatment of Alzheimer disease and other neurodegenerative conditions.

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Section: Discussionsupporting

confidence: 86%

NFAT/Fas signaling mediates the neuronal apoptosis and motor side effects of GSK-3 inhibition in a mouse model of lithium therapy

Gómez‐Sintes¹,

Lucas²

2010

J. Clin. Invest.

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“…In turn, cell death of septohippocampal neurons induced by Aβ in vitro and in vivo requires the presence of p75 NTR [12]. Data from several different models of spinal cord injury, axotomy, deafferentation and ischemia provide strong evidence that Fas activation has a deleterious effect on survival of injured neurons [15,16,[45][46][47][48]. In contrast, in the MPTP model of Parkinson's disease, Fas activation protects dopaminergic neurons from MPTP toxicity, providing the first in vivo evidence that death receptors can act to enhance neuronal survival [49].…”

Section: Death Receptors In Other Diseases and Degenerative Processesmentioning

confidence: 99%

Signaling by death receptors in the nervous system

Haase

Pettmann

Raoul

et al. 2008

Current Opinion in Neurobiology

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SummaryCell death plays an important role both in shaping the developing nervous system and in neurological disease and traumatic injury. In spite of their name, death receptors can trigger either cell death or survival and growth. Recent studies implicate five death receptors -Fas/CD95, TNFR1 (tumor necrosis factor receptor-1), p75 NTR (p75 neurotrophin receptor), DR4 and DR5 (death receptors-4 and -5) -in different aspects of neural development or degeneration. Their roles may be neuroprotective in models of Parkinson's disease, or pro-apoptotic in ALS and stroke. Such different outcomes likely reflect the diversity of transcriptional and post-translational signaling pathways downstream of death receptors in neurons and glia.

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“…Notably, the nuclear factor of activated T cell (NFAT) transcription factors have an important role in the development of the nervous system 7,8 and in the control of the survival/death fate of neurons. [9][10][11][12][13][14] The NFAT family comprises four calcium/calcineurindependent transcription factors that are encoded by four closely related genes. [15][16][17] NFAT proteins are expressed in most mammalian tissues, with the different members of the family being present in distinct but overlapping sets of cell types.…”

mentioning

confidence: 99%

“…Both NFATc3 and NFATc4 have been shown to have either proapoptotic or antiapoptotic effects, depending on the physiologic and cellular context. [9][10][11][12][13][14][20][21][22] However, the mechanisms that regulate their activity in response to apoptotic stimuli and the target genes that mediate their differential effects on neuronal apoptosis are mostly unknown.…”

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confidence: 99%

Control of neuronal apoptosis by reciprocal regulation of NFATc3 and Trim17

et al. 2014

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Neuronal apoptosis induced by survival factor deprivation is strongly regulated at the transcriptional level. Notably, the nuclear factor of activated T cell (NFAT) transcription factors have an important role in the control of the survival/death fate of neurons. However, the mechanisms that regulate NFAT activity in response to apoptotic stimuli and the target genes that mediate their effect on neuronal apoptosis are mostly unknown. In a previous study, we identified Trim17 as a crucial E3 ubiquitin ligase that is necessary and sufficient for neuronal apoptosis. Here, we show that Trim17 binds preferentially SUMOylated forms of NFATc3. Nonetheless, Trim17 does not promote the ubiquitination/degradation of NFATc3. NFAT transcription factors are regulated by calcium/calcineurin-dependent nuclear-cytoplasmic shuttling. Interestingly, Trim17 reduced by twofold the calcium-mediated nuclear localization of NFATc3 and, consistent with this, halved NFATc3 activity, as estimated by luciferase assays and by measurement of target gene expression. Trim17 also inhibited NFATc4 nuclear translocation and activity. NFATc4 is known to induce the expression of survival factors and, as expected, overexpression of NFATc4 protected cerebellar granule neurons from serum/KCl deprivation-induced apoptosis. Inhibition of NFATc4 by Trim17 may thus partially mediate the proapoptotic effect of Trim17. In contrast, overexpression of NFATc3 aggravated neuronal death, whereas knockdown of NFATc3 protected neurons from apoptosis. This proapoptotic effect of NFATc3 might be due to a feedback loop in which NFATc3, but not NFATc4, induces the transcription of the proapoptotic gene Trim17. Indeed, we found that overexpression or silencing of NFATc3, respectively, increased or decreased Trim17 levels, whereas NFATc4 had no significant effect on Trim17 expression. Moreover, we showed that NFATc3 binds to the promoter of the Trim17 gene together with c-Jun. Therefore, our results describe a novel mechanism regulating NFAT transcription factors beyond the calcium/calcineurin-dependent pathway and provide a possible explanation for the opposite effects of NFATc3 and NFATc4 on neuronal apoptosis.

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Deafferentation-Induced Activation of NFAT (Nuclear Factor of Activated T-Cells) in Cochlear Nucleus Neurons during a Developmental Critical Period: A Role for NFATc4-Dependent Apoptosis in the CNS

Cited by 50 publications

References 55 publications

NFAT/Fas signaling mediates the neuronal apoptosis and motor side effects of GSK-3 inhibition in a mouse model of lithium therapy

NFAT/Fas signaling mediates the neuronal apoptosis and motor side effects of GSK-3 inhibition in a mouse model of lithium therapy

Signaling by death receptors in the nervous system

Control of neuronal apoptosis by reciprocal regulation of NFATc3 and Trim17

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