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Volume 17, Number 24,
Issue of December 15, 1997
pp. 9656-9666
Analysis of the Mechanism of Loss of Trophic Factor Dependence
Associated with Neuronal Maturation: A Phenotype Indistinguishable from
Bax Deletion
Received Aug. 7, 1997; revised Sept. 24, 1997; accepted Oct. 6, 1997.
Rachael M. Easton1, 2,
Thomas L. Deckwerth1, 2,
Alexander Sh. Parsadanian1, and
Eugene M. Johnson Jr1, 2
Departments of 1 Neurology and 2 Molecular
Biology and Pharmacology, Washington University School of Medicine, Saint Louis, Missouri 63110
During development, sympathetic neurons are critically dependent on
nerve growth factor (NGF) for survival. Neurons isolated from the
superior cervical ganglia (SCG) of embryonic rodents and maintained for
1 week in vitro undergo programmed cell death in
response to NGF deprivation. As the cells mature in
vitro and in vivo, however, these neurons
develop a resistance to NGF deprivation and become much less acutely
dependent on NGF for survival. Using an in vitro model
of neuronal maturation, we confirmed that SCG neurons maintained in
culture for 3-4 weeks did not experience a dramatic loss in viability
after NGF removal, yet they did undergo the initial biochemical and
genetic changes elicited by NGF deprivation of young neurons. NGF
deprivation of mature neurons produced rapid decreases in glucose
uptake and protein and RNA synthesis rates, increased phosphorylation
of c-Jun, and an increase in c-jun mRNA. Mature neurons,
however, experienced a block in the cell death program before the final
stages of the pathway activated in young neurons, which includes the
induction of c-fos mRNA and characteristic apoptotic
nuclear changes. This maturation-induced block was indistinguishable by
these criteria from the block produced by Bax
deficiency. Expression of Bax in mature neurons restored
the apoptotic pathway, such that after NGF removal,
Bax-overexpressing mature neurons resumed the apoptotic
program, including the induction of c-Fos and passage through a
caspase checkpoint. Thus, a block in the apoptotic program at or near
the BAX checkpoint accounts for the decreased dependence of mature
neurons on neurotrophic factor to maintain survival.
Key words:
neuronal maturation;
trophic factor dependence;
neuronal
cell death;
BAX;
gene expression;
neuronal metabolism
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