Signalling by glial cell line-derived neurotrophic factor (GDNF) requires heparan sulphate glycosaminoglycan.
Glial cell line-derived neurotrophic factor, GDNF, is vital to the development and maintenance of neural tissues; it promotes survival of sympathetic, parasympathetic and spinal motor neurons during development, protects midbrain dopaminergic neurons from apoptosis well enough to be a promising treatment for Parkinson's disease, and controls renal and testicular development. Understanding how GDNF interacts with its target cells is therefore a priority in several fields. Here we show that GDNF requires glycosaminoglycans as well as the already-known components of its receptor complex, c-Ret and GFRalpha-1. Without glycosaminoglcyans, specifically heparan sulphate, c-Ret phosphorylation fails and GDNF cannot induce axonogenesis in neurons, in PC-12 cells, or scatter of epithelial cells. Furthermore, exogenous heparan sulphate inhibits rather than assists GDNF signalling. The involvement of heparan sulphates in GDNF signalling raises the possibility that modulation of heparan expression may modulate signalling by GDNF in vivo.
Barnett
Mark W
MW
Edinburgh University Medical School, Teviot Place, Edinburgh EH8 9AG, UK.
Fisher
Carolyn E
CE
Perona-Wright
Georgia
G
Davies
Jamie A
JA
D000818:Animals; D001369:Axons / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D002809:Chondroitin Sulfates / Q000494:pharmacology; D003871:Dermatan Sulfate / Q000494:pharmacology; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006025:Glycosaminoglycans / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009414:Nerve Growth Factors / Q000378:metabolism / Q000494:pharmacology*; D016716:PC12 Cells; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D002809:Chondroitin Sulfates; D003871:Dermatan Sulfate; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006025:Glycosaminoglycans; D006497:Heparan Sulfate; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C495039:GDNF protein, human; C494987:GFRA1 protein, human; C495040:Gdnf protein, mouse; C495041:Gdnf protein, rat; C494988:Gfra1 protein, mouse; C494989:Gfra1 protein, rat; C494999:Ret protein, mouse; C495001:Ret protein, rat