Correspondence to: Patrik Ernfors, Lab. Mol. Neurobiol., MBB, Karolinska Institutet, Brezeliusväg 3, plan 3, 171 77 Stockholm, Sweden. Tel:46 8 728 7659 Fax:46 8 728 76 56 E-mail:patrik{at}cajal.mbb.ki.se.
During the development of the vertebrate nervous system, a balance is maintained between the formation of neurons and their synapses and neuronal death and synaptic remodeling. Neurotrophic cytokines are known to promote the survival of certain classes of neurons during development. The signaling pathways activated by these cytokines, however, have not been defined. In this issue, B), which is crucial for the survival of cytokine dependent neurons.
In many populations of developing neurons, more than half of the neurons generated die by apoptosis. This is believed to ensure that the correct number and type of neurons innervate target cells. The survival or death decision of neurons appears not to be predetermined, but is instead the consequence of the integration of multiple intracellular signaling pathways activated by external stimuli. Such external stimuli include neurotrophic factors, which are present in limiting quantities. Neurons that obtain an adequate supply of the required neurotrophic factor survive, whereas neurons that are unsuccessful in the competition die.
Neurotrophic cytokines are a family of neurotrophic factors that play an important role in regulating neuronal survival in the developing nervous system. B and that this pathway is essential for the survival of developing sensory neurons. When the authors introduce a NF
B repressor (super-repressor I
B) into embryonic sensory neurons or culture cells lacking the NF
B subunit p65, the neurons show impaired survival response to cytokines. Moreover,
B plays a key role in meditating the survival response of developing sensory neurons to cytokines.
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NF![]() |
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NFB is activated by numerous, diverse signals through a few common intracellular mediators. When cytokines bind to their receptors, the receptor associates with TNF receptor-associated factors (TRAF) 2 or 6, which in turn activates the NF
B-inducing kinase (NIK) via activation of the TAT-associated kinase-1 (TAK1). NIK phosphorylates and activates I
B kinase (IKK) which phosphorylates the inhibitory NF
B binding protein I
B, leading to its degradation and the release and translocation of NF
B to the nucleus (
B activation following the binding of NGF to the p75 neurotrophin receptor (
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NFB is activated in vivo in a number of different animal model systems as well as human neurodegenerative diseases. Whether the elevated NF
B activity contributes to cell survival or cell death has been a controversial issue. Whereas some studies report that elevated activity of NF
B in cerebral ischemia, oxidative stress, and excitotoxicity promote cell death of central neurons (
B in the developing nervous system are more consistent. NF
B activity protects sympathetic neurons against oxidative cell death (
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Neurotrophic Factors and Receptor Signaling |
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In addition to neurotrophic cytokines, the neurotrophic factors of the neurotrophin family are essential for the survival of many kinds of neurons during development and the intracellular signaling pathways mediating their effect are beginning to be understood. The neurotrophin family members, including NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), and neurotrophin-4 (NT4), mediate their effects through the trk tyrosine kinase receptors which activate Ras/MAPK, PI3K/Akt, and PLC signaling pathways (
An important substrate for the survival effects of the neurotrophin receptors is PI3K, which activates the serine-threonine kinase Akt. Akt has been shown to be necessary and sufficient for neurotrophin-mediated neuronal survival of sympathetic neurons (
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Convergence in Neuronal Survival/Death Pathways by Cytokines and Neurotrophins |
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Recent results provide a direct link from cytokine receptors to the PI3K/Akt pathway and from Akt to NFB activity via IKK
-IKKß activation, I
B degradation, and subsequent NF
B nuclear translocation (
B has been shown to participate in NGF-elicited, p75 neurotrophin receptor-mediated neuronal survival, but its relative contribution is not as important as it is in mediating the survival response of developing sensory neurons to cytokines (
B (
How is specificity generated? An essential intracellular mechanism for regulating speed and specificity of signal transduction is the restriction of the subcellular localization of signaling components. This is achieved through anchor proteins bound to specific subcellular structures (proteins or lipids) and scaffold proteins which assemble various signaling components. Recently, two scaffold proteins which could provide a platform for the assembly of NFB signaling components were reported (
The possible participation of the PI3K/Akt pathway in survival signaling by neurotrophic cytokines has yet to be directly examined. Recent results on Akt signaling confirms the importance of context since it can act in different ways in different cell types and following activation by different ligands. For example, Akt is necessary for tumor necrosis factor-mediated NFB activation in epithelial but not in fibroblast cells (
B is activated only after PDGF treatment (
In light of the new results implying an important role for cytokine-induced NFB activation in survival/death signaling during development of the peripheral nervous system, the next issues to be addressed will almost certainly be whether Akt participates in neuronal survival by cytokines, and whether cytokine activation of NF
B involves NIK and/or Akt. A bigger challenge, however, will be to determine when and how cytokine and neurotrophin signaling pathways converge and their consequences for physiological as well as disease processes in the nervous system.
Submitted: 15 December 1999
Accepted: 5 January 2000
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