Phosphatidylinositol 3-kinase is required for the trophic, but not the survival-promoting, actions of NGF on sympathetic neurons

Nerve growth factor (NGF) supports target-dependent survival of sympathetic and other neurons during development; however, the NGF-regulated signaling pathways required for survival are not fully understood. Sympathetic neuro ns are able to abort acutely the cell death pathway initiated by NGF depriv ation at early, as well as late, time points after readdition of NGF. We fo und that NGF-dependent phosphatidylinositol 3-kinase (PI-3-K) activity inhi bited an early cell death event proximal to c-Jun phosphorylation. However, PI-3-K activity was not required for NGF to inhibit the translocation of B ax from the cytoplasm to the mitochondria, nor was it required for NGF to i nhibit the subsequent release of mitochondrial cytochrome c, two events req uired for NGF deprivation-induced apoptosis. MEK/MAPK activity did not acco unt for any of these NGF-dependent events. When subjected to long-term PI-3 -K inhibition in the presence of NGF, the majority of sympathetic neurons d id not die. Those that did die exhibited significant differences in the cha racteristics of death caused by PI-3-K inhibition as compared with NGF depr ivation. Additionally, PI-3-K inhibition in the presence of NGF did not ind uce release of mitochondrial cytochrome c, indicating that these neurons we re unable to complete the apoptotic program. In contrast to its modest effe cts on survival, inhibition of PI-3-K induced marked decreases in somal dia meter and metabolic function, as measured by 3-(4,5-dimethylthiazol-2-yl)-2 ,5-diphenyltetrazolium bromide (MTT) reduction, suggesting that PI-3-K is r equired for the trophic effects of NGF. Therefore, although PI-3-K is impor tant for the trophic effects of NGF, it is not required for survival. Other , or at least additional, signaling pathways contribute to NGF-mediated sur vival of sympathetic neurons.