Neurotrophin Signaling through the p75 Receptor Is Deficient in<i>traf6</i>-/- Mice

Yeiser, E.Carden; Rutkoski, Nancy J.; Naito, Asuka; Inoue, Jun‐ichiro; Carter, Bruce D.

doi:10.1523/jneurosci.1390-04.2004

Cited by 92 publications

(79 citation statements)

References 46 publications

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“…This could contribute to the observed delayed reinnervation through various mechanisms. First, mature BDNF can bind to p75, the level of which remains high in the mutant mice, thus contributing to the apoptosis Gordon, 2001, 2002;Yeiser et al, 2004) detected at 12 d after crush. Second, a high level of the neurotrophin can cause direct inhibition of axonal regeneration.…”

Section: Discussionmentioning

confidence: 99%

Mice Lacking Protease Nexin-1 Show Delayed Structural and Functional Recovery after Sciatic Nerve Crush

Lino¹,

Atanasoski²,

Kvajo³

et al. 2007

J. Neurosci.

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Multiple molecular mechanisms influence nerve regeneration. Because serine proteases were shown to affect peripheral nerve regeneration, we performed nerve crush experiments to study synapse reinnervation in adult mice lacking the serpin protease nexin-1 (PN-1). PN-1 is a potent endogenous inhibitor of thrombin, trypsin, tissue plasminogen activators (tPAs), and urokinase plasminogen activators. Compared with the wild type, a significant delay in synapse reinnervation was detected in PN-1 knock-out (KO) animals, which was associated with both reduced proliferation and increased apoptosis of Schwann cells. Various factors known to affect Schwann cells were also altered. Fibrin deposits, tPA activity, mature BDNF, and the low-affinity p75 neurotrophin receptor were increased in injured sciatic nerves of mutant mice. To test whether the absence of PN-1 in Schwann cells or in the axon caused delay in reinnervation, PN-1 was overexpressed exclusively in the nerves of PN-1 KO mice. Neuronal PN-1 expression did not rescue the delayed reinnervation. The results suggest that Schwann cell-derived PN-1 is crucial for proper reinnervation through its contribution to the autocrine control of proliferation and survival. Thus, the precise balance between distinct proteases and serpins such as PN-1 can modulate the overall impact on the kinetics of recovery.

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Section: Discussionmentioning

confidence: 99%

Mice Lacking Protease Nexin-1 Show Delayed Structural and Functional Recovery after Sciatic Nerve Crush

Lino¹,

Atanasoski²,

Kvajo³

et al. 2007

J. Neurosci.

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“…Recently, another p75 interactor, TRAF6, was shown to be essential for the receptor to induce activation of JNK and the subsequent apoptosis (36). TRAF6 also transduces the signal to NF-B and JNK for several other receptors, such as IL-1␤, RANK, and CD40, through a mechanism involving its oli- gomerization (37).…”

Section: Discussionmentioning

confidence: 99%

Neurotrophin Receptor Interacting Factor (NRIF) Is an Essential Mediator of Apoptotic Signaling by the p75 Neurotrophin Receptor

Linggi

Burke

Williams

et al. 2005

Journal of Biological Chemistry

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Activation of the p75 neurotrophin receptor leads to a variety of effects within the nervous system, including neuronal apoptosis. Both c-Jun N-terminal kinase (JNK) and the tumor suppressor p53 have been reported to be critical for this receptor to induce cell death; however, the mechanisms by which p75 activates these pathways is undetermined. Here we report that the neurotrophin receptor interacting factor (NRIF) is necessary for p75-dependent JNK activation and apoptosis. Upon nerve growth factor withdrawal, nrif؊/؊ sympathetic neurons underwent apoptosis, whereas p75-mediated death was completely abrogated. The lack of cell death correlated with a lack of JNK activation in the nrif؊/؊ neurons, suggesting that NRIF is a selective mediator for p75-dependent JNK activation and apoptosis. Moreover, we document that NRIF expression is sufficient to induce cell death through a mechanism that requires p53. Taken together, these results establish NRIF as an essential component of the p75 apoptotic pathway.The p75 neurotrophin receptor is a pleiotropic signaling molecule that regulates cellular survival, neurite outgrowth, and myelin formation (1). This founding member of the tumor necrosis factor receptor superfamily can directly bind all of the neurotrophins, including nerve growth factor (NGF), 1 brainderived neurotrophic factor (BDNF), and neurotrophin-3 and -4 (NT-3, NT-4), but it also functions as a co-receptor in a variety of protein complexes. p75 can interact with TrkA to form a high affinity neurotrophin binding site (2) and enhance survival signaling (3). It can also associate with the Nogo receptor and Lingo-1 and, upon interaction with myelin proteins, block neurite outgrowth (4, 5), and, together with Sortilin, the neurotensin 3 receptor, it binds the proform of NGF and initiates apoptosis (6). The divergent cellular responses depend on the receptor complex as well as the cellular context. For example, sympathetic neurons of superior cervical ganglia undergo a period of programmed cell death during ontogenesis, and NGF, supplied by the tissues innervated, prevents the loss of these neurons through binding to a p75-TrkA complex (7). In contrast, specific activation of p75 (8) or a p75-sortilin complex (6) induces apoptosis in the neurons. Genetic deletion of p75 prevents the normal period of cell death in the developing superior cervical ganglia (8, 9), thus demonstrating the key role of this receptor in regulating the survival of this neuronal population.How p75 initiates this variety of biological effects is not well understood; however, the stress kinase c-Jun N-terminal kinase, JNK, has been suggested to play a role in mediating this apoptotic signal. Neurotrophin activation of JNK through p75 correlates with the induction of cell death (43) and inhibition of the kinase prevents the receptor from killing (23, 10). Interestingly, c-Jun, the downstream target of the kinase, is not required for the receptor to activate apoptosis (11); however, other JNK substrates have been implicated in the p75 death ...

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“…31 Deletion of TRAF6 resulted in a loss of the neurotrophincoupled induction of apoptosis in both schwann cells and sympathetic neurons of TRAF6À/À mice. 34 It is currently unknown how either the p75 NTR or trk A receptors converge to activate the IKK complex. Adaptor proteins may be involved in forming signaling complexes with TRAF6 and helping to recruit it to the p75 NTR .…”

Section: Growth Factor Signalingmentioning

confidence: 99%

Roles for NF-κB in nerve cell survival, plasticity, and disease

2006

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Here we review evidence of roles for NF-jB in the regulation of developmental and synaptic plasticity, and cell survival in physiological and pathological settings. Signaling pathways modulating NF-jB activity include those engaged by neurotrophic factors, neurotransmitters, electrical activity, cytokines, and oxidative stress. Emerging findings support a pivotal role for NF-jB as a mediator of transcription-dependent enduring changes in the structure and function of neuronal circuits. Distinct subunits of NF-jB may uniquely affect cognition and behavior by regulating specific target genes. NF-jB activation can prevent the death of neurons by inducing the production of antiapoptotic proteins such as Bcl-2, IAPs and manganese superoxide dismutase (Mn-SOD). Recent findings indicate that NF-jB plays important roles in disorders such as epilepsy, stroke, Alzheimer's and Parkinson's diseases, as well as oncogenesis. Molecular pathways upstream and downstream of NF-jB in neurons are being elucidated and may provide novel targets for therapeutic intervention in various neurological disorders.

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Neurotrophin Signaling through the p75 Receptor Is Deficient intraf6-/- Mice

Cited by 92 publications

References 46 publications

Mice Lacking Protease Nexin-1 Show Delayed Structural and Functional Recovery after Sciatic Nerve Crush

Mice Lacking Protease Nexin-1 Show Delayed Structural and Functional Recovery after Sciatic Nerve Crush

Neurotrophin Receptor Interacting Factor (NRIF) Is an Essential Mediator of Apoptotic Signaling by the p75 Neurotrophin Receptor

Roles for NF-κB in nerve cell survival, plasticity, and disease

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