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PMID: 9822741 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Glial cell line-derived neurotrophic factor requires transforming growth factor-beta for exerting its full neurotrophic potential on peripheral and CNS neurons.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 18 ·No. 23 ·1998-12-01 ·Pages 9822-34

Krieglstein K, Henheik P, Farkas L, Jaszai J, Galter D, Krohn K, Unsicker K

Abstract

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-beta. Immunoneutralization of endogenous TGF-beta provided by serum or TGF-beta-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-beta identifies 60 pg/ml of either factor combined with 2 ng/ml of the other factor as the EC50. GDNF/TGF-beta 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-beta 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 alpha. The biological significance of the trophic synergism of GDNF and TGF-beta is underscored by colocalization of the receptors for TGF-beta and GDNF on all investigated GDNF-responsive neuron populations in vivo. Moreover, the in vivo relevance of the TGF-beta/GDNF synergism is highlighted by the co-storage of TGF-beta 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.

MeSH Terms
Androstadienes/pharmacology Animals Cell Survival/drug effects Cells, Cultured Chick Embryo Chromaffin Cells/cytology,drug effects Dopamine/physiology Dose-Response Relationship, Drug Drug Synergism Enzyme Inhibitors/pharmacology Exocytosis/drug effects Fetus/cytology Gene Expression/physiology Glial Cell Line-Derived Neurotrophic Factor Glycosylphosphatidylinositols/physiology Motor Neurons/cytology,drug effects Nerve Growth Factors Nerve Tissue Proteins/analysis,pharmacology Neuroprotective Agents/analysis,pharmacology Phosphatidylinositol Diacylglycerol-Lyase Phosphoinositide Phospholipase C Rats Rats, Wistar Signal Transduction/physiology Transforming Growth Factor beta/genetics,pharmacology Type C Phospholipases/pharmacology Wortmannin
Chemicals
Androstadienes Enzyme Inhibitors Gdnf protein, rat Glial Cell Line-Derived Neurotrophic Factor Glycosylphosphatidylinositols Nerve Growth Factors Nerve Tissue Proteins Neuroprotective Agents Transforming Growth Factor beta Type C Phospholipases Phosphoinositide Phospholipase C Phosphatidylinositol Diacylglycerol-Lyase Dopamine Wortmannin
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Krieglstein K
Department of Neuroanatomy, University of Heidelberg, D-69120 Heidelberg, Germany.
Henheik P
Farkas L
Jaszai J
Galter D
Krohn K
Unsicker K
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
0270-6474
Published
1998-12-01
Pages
9822-34
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6793316
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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