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Published online 7 October 2002. doi:10.1083/jcb.200203115
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© The Rockefeller University Press, 0021-9525/2002/10/157 $5.00
The Journal of Cell Biology, Volume 159, Number 1, 157-167

Article

 TGFß induces GDNF responsiveness in neurons by recruitment of GFR{alpha}1 to the plasma membrane

H. Peterziel1, K. Unsicker1 and K. Krieglstein2

1 Department of Neuroanatomy, IZN, University of Heidelberg, D-69115 Heidelberg, Germany
2 Department of Neuroanatomy, University of Göttingen, D-37075 Göttingen, Germany

Address correspondence to Dr. Heike Peterziel, Department of Neuroanatomy and Center for Neurosciences (IZN), Im Neuenheimer Feld 307, 2.OG, D-69120 Heidelberg, Germany. Tel.: 49-6221-548314. Fax: 49-6221-545604. E-mail: heike.peterziel{at}urz.uni-heidelberg.de

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)ß. Using primary neurons (chick E8 ciliary) we show that the combination of GDNF plus TGFß 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 TGFß, pretreatment with TGFß confers GDNF responsiveness to the cells. This is not due to upregulation of GDNF receptors mRNA and protein, but to TGFß-induced recruitment of the glycosyl-phosphatidylinositol-anchored GDNF receptor (GFR){alpha}1 to the plasma membrane. This is supported by the fact that GDNF in the presence of a soluble GFR{alpha}1 can promote survival in the absence of TGFß. Our data suggest that TGFß is involved in GFR{alpha}1 membrane translocation, thereby permitting GDNF signaling and neurotrophic effects.

Key Words: neurotrophic factors; lipid raft; GFR{alpha}1; tyrosine kinases; MAPK pathway


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