Inhibition of apoptotic signaling cascades causes loss of trophic factor dependence during neuronal maturation

During development, neurons are acutely dependent on target-derived trophic factors for survival. This dependence on trophic support decreases dramati cally with maturation in several neuronal populations, including sympatheti c neurons. Analyses of nerve growth factor deprivation in immature and matu re sympathetic neurons indicate that maturation aborts the cell death pathw ay at a point that is mechanistically indistinguishable from Bas deletion. How ever, neither the mRNA nor protein level of BAX changes with neuronal m aturation. Therefore, BAX must be regulated posttranslationally in mature n eurons, Nerve growth factor deprivation in immature sympathetic neurons induces two parallel processes: (a) a protein synthesis-dependent, caspase-independent translocation of BAX from the cytosol to mitochondria, followed by mitocho ndrial membrane integration and loss of cytochrome c; and (b) the developme nt of competence-to-die, which requires neither macromolecular synthesis no r BAX expression. Activation of both signaling pathways is required for cas pase activation and apoptosis in immature sympathetic neurons. In contrast, nerve growth factor withdrawal in mature sympathetic neurons did not induc e the translocation of either BAX or cytochrome c. Moreover, mature neurons did not develop competence-to-die with cytoplasmic accumulation of cytochr ome c, Therefore, inhibition of both BAX-dependent cytochrome c release and the development of competence-to-die contributed to the loss of trophic fa ctor dependence associated with neuronal maturation.