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The Journal of Neuroscience, December 1, 1998, 18(23):9822-9834
Glial Cell Line-Derived Neurotrophic Factor Requires Transforming
Growth Factor- for Exerting Its Full Neurotrophic Potential on
Peripheral and CNS Neurons
Kerstin
Krieglstein1,
Prisca
Henheik1,
Lilla
Farkas1,
Jozsef
Jaszai1,
Dagmar
Galter1,
Knut
Krohn2, and
Klaus
Unsicker1
1 Department of Neuroanatomy, University of Heidelberg,
D-69120 Heidelberg, Germany and 2 Center for Internal
Medicine, University of Leipzig, D-04103 Leipzig, Germany
Numerous studies have suggested that glial cell line-derived
neurotrophic factor (GDNF) is a potent neurotrophic molecule. We show
now on a variety of cultured neurons including peripheral autonomic,
sensory, and CNS dopaminergic neurons that GDNF is not trophically
active unless supplemented with TGF- . Immunoneutralization of
endogenous TGF- provided by serum or TGF--secreting cells, as
e.g., neurons, in culture abolishes the neurotrophic effect of GDNF.
The dose-response relationship required for the synergistic effect of
GDNF and TGF- identifies 60 pg/ml of either factor combined with 2 ng/ml of the other factor as the EC50. GDNF/TGF- signaling employs activation of phosphatidylinositol-3 (PI-3) kinase as an intermediate step as shown by the effect of the specific PI-3 kinase inhibitor wortmannin. The synergistic action of GDNF and
TGF- involves protection of glycosylphosphatidylinositol (GPI)-linked receptors as shown by the restoration of their
trophic effects after phosphatidylinositol-specific phospholipase
C-mediated hydrolysis of GPI-anchored GDNF family receptor  .
The biological significance of the trophic synergism of GDNF and
TGF- is underscored by colocalization of the receptors for TGF-
and GDNF on all investigated GDNF-responsive neuron populations
in vivo. Moreover, the in vivo relevance
of the TGF-/GDNF synergism is highlighted by the co-storage of
TGF- and GDNF in secretory vesicles of a model neuron, the chromaffin cell, and their activity-dependent release. Our results broaden the definition of a neurotrophic factor by incorporating the
possibility that two factors that lack a neurotrophic activity when
acting separately become neurotrophic when acting in concert. Moreover,
our data may have a substantial impact on the treatment of
neurodegenerative diseases.
Key words:
motoneurons; dopaminergic neurons; neurotrophic factors; exocytosis; chromaffin cells; neurodegenerative disease; signal
transduction
Copyright © 1998 Society for Neuroscience 0270-6474/98/18239822-13$05.00/0
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