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© The Rockefeller University Press, 0021-9525/2000//1011 $5.00
The Journal of Cell Biology, Volume 149, Number 5, , 2000 1011-1018

Brief Report

Inhibition of Apoptotic Signaling Cascades Causes Loss of Trophic Factor Dependence during Neuronal Maturation



Girish V. Putchaa, Mohanish Deshmukha, and Eugene M. Johnson, Jr.a

a Department of Neurology and Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, 4566 Scott Ave., Box 8103, St. Louis, MO 63110.(314) 747-1772(314) 362-3926

ejohnson{at}pcg.wustl.edu

During development, neurons are acutely dependent on target-derived trophic factors for survival. This dependence on trophic support decreases dramatically with maturation in several neuronal populations, including sympathetic neurons. Analyses of nerve growth factor deprivation in immature and mature sympathetic neurons indicate that maturation aborts the cell death pathway at a point that is mechanistically indistinguishable from Bax deletion. However, neither the mRNA nor protein level of BAX changes with neuronal maturation. Therefore, BAX must be regulated posttranslationally in mature neurons.

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 mitochondrial membrane integration and loss of cytochrome c; and (b) the development of competence-to-die, which requires neither macromolecular synthesis nor BAX expression. Activation of both signaling pathways is required for caspase activation and apoptosis in immature sympathetic neurons. In contrast, nerve growth factor withdrawal in mature sympathetic neurons did not induce the translocation of either BAX or cytochrome c. Moreover, mature neurons did not develop competence-to-die with cytoplasmic accumulation of cytochrome c. Therefore, inhibition of both BAX-dependent cytochrome c release and the development of competence-to-die contributed to the loss of trophic factor dependence associated with neuronal maturation.

Key Words: BAX • caspase • cytochrome c • mitochondria • neurotrophin

© 2000 The Rockefeller University Press

Abbreviations used in this paper: BAF, boc-aspartyl(OMe)-fluoromethylketone; DIV, days in vitro; HM, heavy membrane.


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