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Volume 16, Number 13,
Issue of July 1, 1996
pp. 4174-4185
Copyright ©1996 Society for Neuroscience
TGF- -Induced Apoptosis of Cerebellar Granule Neurons Is
Prevented by Depolarization
Received Dec. 28, 1995; revised March 20, 1996; accepted April 5, 1996.
Ariane de Luca1,
Michael Weller2, and
Adriano Fontana1
1 Section of Clinical Immunology, Department of
Internal Medicine, University Hospital, CH-8044 Zürich,
Switzerland, and 2 Department of Neurology, School of
Medicine, University of Tübingen, D-72076 Tübingen,
Germany
The regulation of programmed cell death in the developing nervous
system involves target-derived survival factors, afferent synaptic
activity, and hormone- and cytokine-dependent signaling. Cultured
immature cerebellar granule neurons die by apoptosis within several
days in vitro unless maintained in depolarizing (high)
concentrations of potassium (25 mM
K+). Here we report that transforming growth
factors (TGF)- 1, -2,
and -3 accelerate apoptosis of these neurons
when maintained in physiological (low) K+ medium
(5 mM K+) as assessed by
measures of viability, quantitative DNA fragmentation, and nuclear
morphology. TGF--induced apoptosis of these neurons is not blocked
by CNTF and LIF, cytokines that enhance neuronal survival when applied
alone, or by IGF-I, which prevents apoptosis upon potassium withdrawal.
In contrast, neurons that differentiate in high
K+ medium for several days in vitro
acquire resistance to TGF--mediated cell death. Granule neurons
maintained in either low or high K+ medium
produce latent, but not bioactive, TGF-1 and
-2. Because neutralizing TGF- antibodies
fail to augment survival of low K+ neurons, the
cerebellar neurons are apparently unable to activate latent TGF-.
Thus, apoptosis of low K+ neurons is not
attributable to endogenous production of TGF-. Taken together, our
data suggest that TGF- may limit the expansion of postmitotic
neuronal precursor populations by promoting their apoptosis but
may support survival of those neurons that have maturated,
differentiated, and established supportive synaptic connectivity.
Key words:
apoptosis;
cerebellum;
depolarization;
maturation-dependence;
potassium;
TGF-
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