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

J Neurosci. 1998 Dec 1;18(23):9822-34. doi: 10.1523/JNEUROSCI.18-23-09822.1998.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / pharmacology
  • Animals
  • Cell Survival / drug effects
  • Cells, Cultured
  • Chick Embryo
  • Chromaffin Cells / cytology
  • Chromaffin Cells / 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
  • Motor Neurons / drug effects*
  • Nerve Growth Factors*
  • Nerve Tissue Proteins / analysis
  • Nerve Tissue Proteins / pharmacology*
  • Neuroprotective Agents / analysis
  • Neuroprotective Agents / pharmacology*
  • Phosphatidylinositol Diacylglycerol-Lyase
  • Phosphoinositide Phospholipase C
  • Rats
  • Rats, Wistar
  • Signal Transduction / physiology
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / pharmacology*
  • Type C Phospholipases / pharmacology
  • Wortmannin

Substances

  • 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