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Volume 16, Number 13, Issue of July 1, 1996 pp. 4174-4185
Copyright ©1996 Society for Neuroscience

TGF-beta -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)-beta 1, -beta 2, and -beta 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-beta -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-beta -mediated cell death. Granule neurons maintained in either low or high K+ medium produce latent, but not bioactive, TGF-beta 1 and -beta 2. Because neutralizing TGF-beta antibodies fail to augment survival of low K+ neurons, the cerebellar neurons are apparently unable to activate latent TGF-beta . Thus, apoptosis of low K+ neurons is not attributable to endogenous production of TGF-beta . Taken together, our data suggest that TGF-beta 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-beta




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