TGFbeta induces GDNF responsiveness in neurons by recruitment of GFRalpha1 to the plasma membrane.
We have previously shown that the neurotrophic effect of glial cell line-derived neurotrophic factor (GDNF) in vitro and in vivo requires the presence of transforming growth factor (TGF)beta. Using primary neurons (chick E8 ciliary) we show that the combination of GDNF plus TGFbeta promotes survival, whereas the single factors do not. This cooperative effect is inhibited by blocking the extracellular signal-regulated kinase (ERK)/MAPK pathway, but not by interfering with the PI3 kinase signaling cascade. Although there is no functional GDNF signaling in the absence of TGFbeta, pretreatment with TGFbeta confers GDNF responsiveness to the cells. This is not due to upregulation of GDNF receptors mRNA and protein, but to TGFbeta-induced recruitment of the glycosyl-phosphatidylinositol-anchored GDNF receptor (GFR)alpha1 to the plasma membrane. This is supported by the fact that GDNF in the presence of a soluble GFRalpha1 can promote survival in the absence of TGFbeta. Our data suggest that TGFbeta is involved in GFRalpha1 membrane translocation, thereby permitting GDNF signaling and neurotrophic effects.
Peterziel
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Department of Neuroanatomy, IZN, University of Heidelberg, D-69115 Heidelberg, Germany. heike.peterziel@urz.uni-heidelberg.de
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Krieglstein
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D000818:Animals; D020126:Brefeldin A / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D002642:Chick Embryo; D029721:Drosophila Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D021962:Membrane Microdomains / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*
D029721:Drosophila Proteins; C495039:GDNF protein, human; C494987:GFRA1 protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D011500:Protein Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; D020126:Brefeldin A; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; D020928:Mitogen-Activated Protein Kinases