| Summary: | Neurons are generated in excess in the developing vertebrate peripheral nervous system, and the superfluous neurons are lost during a phase of programmed cell death that occurs shortly after they innervate their targets. Using a variety of in vitro and in vivo experimental approaches in wild type and transgenic mice, I have demonstrated that tumour necrosis factor a (TNFa) has opposite effects on neuronal survival at different stages in development. Early during the period of naturally occurring neuronal death it enhances the survival of sensory and sympathetic neurons, whereas later in development it promotes, by an autocrine mechanism, the death of neurons that fail to obtain sufficient target-derived neurotrophic factor to sustain their survival. The early survival-enhancing effect of TNFa and the survivalenhancing effect of nerve growth factor (NGF) are mediated by activation of the transcription factor NF-kB in the peripheral nervous system. However, in the case of retinal ganglion cells and motoneurons of the developing central nervous system, NF-kB appears to play a role promoting cell death during development. Finally, I demonstrated that Bad, a member of the Bcl-2 family of proteins, is required for programmed cell death of many sensory and sympathetic neurons during development. These findings show that the same extracellular and intracellular signalling proteins can exert opposite effects on neuronal survival in different locations in the nervous system and at different stages of development.
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