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The Journal of Neuroscience, October 1, 2000, 20(19):7228-7237
Phosphatidylinositol 3-Kinase Is Required for the Trophic, But Not the Survival-Promoting, Actions of NGF on Sympathetic Neurons
Brian A. Tsui-Pierchala, Girish V. Putcha, and Eugene M. Johnson Jr Department of Neurology and Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110
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 neurons are able to abort acutely the cell death pathway initiated by NGF deprivation at early, as well as late, time points after readdition of NGF. We found that NGF-dependent phosphatidylinositol 3-kinase (PI-3-K) activity inhibited 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 Bax from the cytoplasm to the mitochondria, nor was it required for NGF to inhibit the subsequent release of mitochondrial cytochrome c, two events required for NGF deprivation-induced apoptosis. MEK/MAPK activity did not account 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 did not die. Those that did die exhibited significant differences in the characteristics of death caused by PI-3-K inhibition as compared with NGF deprivation. Additionally, PI-3-K inhibition in the presence of NGF did not induce release of mitochondrial cytochrome c, indicating that these neurons were unable to complete the apoptotic program. In contrast to its modest effects on survival, inhibition of PI-3-K induced marked decreases in somal diameter and metabolic function, as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphen-yltetrazolium bromide (MTT) reduction, suggesting that PI-3-K is required for the trophic effects of NGF. Therefore, although PI-3-K is important for the trophic effects of NGF, it is not required for survival. Other, or at least additional, signaling pathways contribute to NGF-mediated survival of sympathetic neurons.
Key words: phosphatidylinositol 3-kinase; sympathetic neurons; NGF; Bax; cytochrome c; apoptosis
Copyright © 2000 Society for Neuroscience 0270-6474/00/20197228-10$05.00/0
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