DEATH OF OLIGODENDROCYTES MEDIATED BY THE INTERACTION OF NERVE GROWTH-FACTOR WITH ITS RECEPTOR P75

MEMBERS of the nerve growth factor (NGF) family promote the survival o f neurons during development(1). NGF specifically activates the recept or trkA, initiating a signal transduction cascade which ultimately blo cks cell death. Here we show that NGF can have the opposite effect, in ducing the death of mature oligodendrocytes cultured from postnatal ra t cerebral cortex. This effect was highly specific, because NGF had no effect on oligodendrocyte precursors and astrocytes. Other neurotroph ins such as brain-derived neurotrophin factor (BDNF) and neurotrophin- 3 (NT-3) did not induce cell death. NGF binding to mature oligodendroc ytes expressing the p75 neurotrophin receptor, but not trkA, resulted in a sustained increase of intracellular ceramide and c-Jun amino-term inal kinase (JNK) activity, which are thought to participate in a sign al transduction pathway leading to cell death. Taken together, these r esults indicate that NGF has the ability to promote cell death in spec ific cell types through a ligand-dependent signalling mechanism involv ing the p75 neurotrophin receptor.