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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 re- modeling. Neurotrophic cytokines are known to promote the survival of certain classes of neurons during develop- ment. The signaling pathways activated by these cyto- kines, however, have not been defined. In this issue, Mid- dleton et al. (2000) provides evidence that neurotrophic cytokines activate the transcription factor nuclear factor kappa B (NF k B), which is crucial for the survival of cyto- kine dependent neurons. In many populations of developing neurons, more than half of the neurons generated die by apoptosis. This is be- lieved to ensure that the correct number and type of neu- rons 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 intracellu- lar 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 sur- vive, whereas neurons that are unsuccessful in the compe- tition die. Neurotrophic cytokines are a family of neurotrophic factors that play an important role in regulating neuronal survival in the developing nervous system. Middleton et al. (2000) describes new results showing that neurotrophic cy- tokines (including ciliary neurotrophic factor (CNTF); leu- kemia inhibitory factor (LIF); cardiotrophin-1 (CT-1); and interleukin-6 (IL-6)) activate NF k B and that this pathway is essential for the survival of developing sensory neurons. When the authors introduce a NF k B repressor (super- repressor I k B) into embryonic sensory neurons or culture cells lacking the NF k B subunit p65, the neurons show im- paired survival response to cytokines. Moreover, Middle- ton et al. (2000) finds that p65 null mutant mice display an increased apoptosis of cytokine-dependent neurons during development in vivo. They therefore conclude that NF k B plays a key role in meditating the survival response of de- veloping sensory neurons to cytokines.

Nuclear Factor-κb to the Rescue of Cytokine-Induced Neuronal Survival