Structural determinants of heparan sulphate modulation of GDNF signalling.
Glial cell line-derived neurotrophic factor (GDNF) has many functions including regulation of kidney morphogenesis and of neuron growth and survival in the enteric, sensory and central nervous systems. Reports of GDNF being used against Parkinson's disease in human patients have sparked intense clinical interest in GDNF signalling. We recently showed that GDNF signalling requires cell surface heparan sulphate glycosaminoglycans (Barnett et al., 2002, J. Cell Sci. 115, 4495-4503). Here we use exogenous modified heparins to determine those structural features required to inhibit GDNF signalling in ex vivo assays. 2-O-sulphate groups were found to impart high activity but were not absolute requirements for the inhibition of GDNF signalling. These findings may explain the similarities between the phenotypes of transgenic mice lacking GDNF and those lacking heparan sulphate 2-sulphotransferase, the enzyme responsible for achieving 2-O-sulphation of uronic acids in vivo.
Davies
J A
JA
Anatomy Building, Edinburgh University College of Medicine, Teviot Place, Edinburgh EH8 9AG, UK. jamie.davies@ed.ac.uk
Yates
E A
EA
Turnbull
J E
JE
D000818:Animals; D002417:Cattle; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006493:Heparin / Q000737:chemistry; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009414:Nerve Growth Factors / Q000378:metabolism*; D009844:Oligosaccharides / Q000737:chemistry; D016716:PC12 Cells; D010641:Phenotype; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction; D013431:Sulfates / Q000737:chemistry; D015238:Sulfotransferases / Q000378:metabolism; D014574:Uronic Acids / Q000737:chemistry
D051100:Glial Cell Line-Derived Neurotrophic Factor; D006493:Heparin; D006497:Heparan Sulfate; D009414:Nerve Growth Factors; D009844:Oligosaccharides; D013431:Sulfates; D015238:Sulfotransferases; D014574:Uronic Acids; C495039:GDNF protein, human; C495040:Gdnf protein, mouse; C495041:Gdnf protein, rat; C021350:heparitin sulfotransferase