 |
 Previous Article | Next Article 
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
This article has been cited by other articles:
|
|
|
|
 
J. Strelau, A. Strzelczyk, P. Rusu, G. Bendner, S. Wiese, F. Diella, A. L. Altick, C. S. von Bartheld, R. Klein, M. Sendtner, et al.
Progressive Postnatal Motoneuron Loss in Mice Lacking GDF-15
J. Neurosci.,
October 28, 2009;
29(43):
13640 - 13648.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Song, G. Chen, Y. Wang, G. Mao, Y. Wang, and H. Bai
Chemically defined sequential culture media for TH+ cell derivation from human embryonic stem cells
Mol. Hum. Reprod.,
November 1, 2008;
14(11):
619 - 625.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Feng and C.-P. Ko
Schwann Cells Promote Synaptogenesis at the Neuromuscular Junction via Transforming Growth Factor-{beta}1
J. Neurosci.,
September 24, 2008;
28(39):
9599 - 9609.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Murase and R. D. McKay
A specific survival response in dopamine neurons at most risk in Parkinson's disease.
J. Neurosci.,
September 20, 2006;
26(38):
9750 - 9760.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Vargas-Leal, R. Bruno, T. Derfuss, M. Krumbholz, R. Hohlfeld, and E. Meinl
Expression and Function of Glial Cell Line-Derived Neurotrophic Factor Family Ligands and Their Receptors on Human Immune Cells
J. Immunol.,
August 15, 2005;
175(4):
2301 - 2308.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. M. Farkas, N. Dunker, E. Roussa, K. Unsicker, and K. Krieglstein
Transforming Growth Factor-{beta}s Are Essential for the Development of Midbrain Dopaminergic Neurons In Vitro and In Vivo
J. Neurosci.,
June 15, 2003;
23(12):
5178 - 5186.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Subramaniam, J. Strelau, and K. Unsicker
Growth Differentiation Factor-15 Prevents Low Potassium-induced Cell Death of Cerebellar Granule Neurons by Differential Regulation of Akt and ERK Pathways
J. Biol. Chem.,
March 7, 2003;
278(11):
8904 - 8912.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. M. Dhandapani, V. B. Mahesh, and D. W. Brann
Astrocytes and Brain Function: Implications for Reproduction
Experimental Biology and Medicine,
March 1, 2003;
228(3):
253 - 260.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Peterziel, K. Unsicker, and K. Krieglstein
TGF{beta} induces GDNF responsiveness in neurons by recruitment of GFR{alpha}1 to the plasma membrane
J. Cell Biol.,
October 14, 2002;
159(1):
157 - 167.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Grammas and R. Ovase
Cerebrovascular Transforming Growth Factor-{beta} Contributes to Inflammation in the Alzheimer's Disease Brain
Am. J. Pathol.,
May 1, 2002;
160(5):
1583 - 1587.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. F. Espejo, M. C. Gonzalez-Albo, J.-P. Moraes, F. El Banoua, J. A. Flores, and I. Caraballo
Functional Regeneration in a Rat Parkinson's Model after Intrastriatal Grafts of Glial Cell Line-Derived Neurotrophic Factor and Transforming Growth Factor beta 1-Expressing Extra-Adrenal Chromaffin Cells of the Zuckerkandl's Organ
J. Neurosci.,
December 15, 2001;
21(24):
9888 - 9895.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Boillee, J. Cadusseau, M. Coulpier, G. Grannec, and M.-P. Junier
Transforming Growth Factor {alpha}: A Promoter of Motoneuron Survival of Potential Biological Relevance
J. Neurosci.,
September 15, 2001;
21(18):
7079 - 7088.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Dunker, N. Schuster, and K. Krieglstein
TGF-{beta} modulates programmed cell death in the retina of the developing chick embryo
Development,
June 1, 2001;
128(11):
1933 - 1942.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Nicole, C. Ali, F. Docagne, L. Plawinski, E. T. MacKenzie, D. Vivien, and A. Buisson
Neuroprotection Mediated by Glial Cell Line-Derived Neurotrophic Factor: Involvement of a Reduction of NMDA-Induced Calcium Influx by the Mitogen-Activated Protein Kinase Pathway
J. Neurosci.,
May 1, 2001;
21(9):
3024 - 3033.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. T. Erickson, T. A. Brosenitsch, and D. M. Katz
Brain-Derived Neurotrophic Factor and Glial Cell Line-Derived Neurotrophic Factor Are Required Simultaneously for Survival of Dopaminergic Primary Sensory Neurons In Vivo
J. Neurosci.,
January 15, 2001;
21(2):
581 - 589.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Strelau, A. Sullivan, M. Bottner, P. Lingor, E. Falkenstein, C. Suter-Crazzolara, D. Galter, J. Jaszai, K. Krieglstein, and K. Unsicker
Growth/Differentiation Factor-15/Macrophage Inhibitory Cytokine-1 Is a Novel Trophic Factor for Midbrain Dopaminergic Neurons In Vivo
J. Neurosci.,
December 1, 2000;
20(23):
8597 - 8603.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. J. Symes, R. L. Pitts, J. Conover, K. Kos, and J. Coulombe
Synergy of Activin and Ciliary Neurotrophic Factor Signaling Pathways in the Induction of Vasoactive Intestinal Peptide Gene Expression
Mol. Endocrinol.,
March 1, 2000;
14(3):
429 - 439.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
D. Worley, J. Pisano, E. Choi, L Walus, C. Hession, R. Cate, M Sanicola, and S. Birren
Developmental regulation of GDNF response and receptor expression in the enteric nervous system
Development,
January 10, 2000;
127(20):
4383 - 4393.
[Abstract]
[PDF]
|
|
|
|
|
|
|
A. Schober, R. Hertel, U. Arumae, L. Farkas, J. Jaszai, K. Krieglstein, M. Saarma, and K. Unsicker
Glial Cell Line-Derived Neurotrophic Factor Rescues Target-Deprived Sympathetic Spinal Cord Neurons But Requires Transforming Growth Factor-beta as Cofactor In Vivo
J. Neurosci.,
March 15, 1999;
19(6):
2008 - 2015.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
