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Neurturin responsiveness requires a GPI-linked receptor and the Ret receptor tyrosine kinase

Nature volume 387, pages 721–724 (1997)Cite this article

Abstract

Neurturin (NTN)1 is a recently identified homologue of glial-cell-line-derived neurotrophic factor (GDNF)2. Both factors promote the survival of a variety of neurons1,2,3,4,5, and GDNF is required for the development of the enteric nervous system and kidney6,7,8. GDNF signals through a receptor complex consisting of the receptor tyrosine kinase Ret and a glycosyl-phosphatidylinositol (GPI)-linked receptor termed GDNFR-α9,10,11,12,13. Here we report the cloning of a new GPI-linked receptor termed NTNR-α that is homologous with GDNFR-α and is widely expressed in the nervous system and other tissues. By using microinjection to introduce expression plasmids into neurons, we show that coexpression of NTNR-α with Ret confers a survival response to neurturin but not GDNF, and that coexpression of GDNFR-α with Ret confers a survival response to GDNF but not neurturin. Our findings indicate that GDNF and neurturin promote neuronal survival by signalling through similar multicomponent receptors that consist of a common receptor tyrosine kinase and a member of a GPI-linked family of receptors that determines ligand specificity.

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Figure 1: Aligned sequences of chicken GDNFR-α and NTNR-α.
Figure 2: a, RT–PCR detection of endogenous c-Ret, GDNFR-α and NTNR-α transcripts in mouse P4 SCG neurons (which do not respond to GDNF and neurturin) and P4 mouse nodose neurons (which do respond to these factors).
Figure 3: Survival of E6 chicken nodose ganglion neurons grown with either neurturin or BDNF for 36 h.
Figure 4: Analysis of the expression of GDNFR-α and NTNR-α mRNAs by northern blotting.

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References

  1. Kotzbauer, P. T.et al. Neurturin, a relative of glial-cell-line-derived neurotrophic factor. Nature 384, 467–470 (1996).

    Article  ADS  CAS  Google Scholar 

  2. Lin, L. H., Doherty, D. H., Lile, J. D., Bektesh, S. & Collins, F. GDNF: A glial cell-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260, 1130–1132 (1993).

    Article  ADS  CAS  Google Scholar 

  3. Henderson, C. E.et al. GDNF: A potent survival factor for motoneurons present in peripheral nerve and muscle. Science 266, 1062–1064 (1994).

    Article  ADS  CAS  Google Scholar 

  4. Buj-Bello, A., Buchman, V. L., Horton, A., Rosenthal, A. & Davies, A. M. GDNF is an age-specific survival factor for sensory and autonomic neurons. Neuron 15, 821–828 (1995).

    Article  CAS  Google Scholar 

  5. Trupp, M.et al. Peripheral expression and biological activities of GDNF, a new neurotrophic factor for avian and mammalian peripheral neurons. J. Cell Biol. 130, 137–148 (1995).

    Article  CAS  Google Scholar 

  6. Moore, M. W.et al. Renal and neuronal abnormalities in mice lacking GDNF. Nature 382, 76–79 (1996).

    Article  ADS  CAS  Google Scholar 

  7. Pichel, J. G.et al. Defects in enteric innervation and kidney development in mice lacking GDNF. Nature 382, 73–76 (1996).

    Article  ADS  CAS  Google Scholar 

  8. Sanchez, M. P.et al. Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature 382, 70–73 (1996).

    Article  ADS  CAS  Google Scholar 

  9. Treanor, J.et al. Characterization of a receptor for glial cell line-derived neurotropic factor. Nature 382, 80–83 (1996).

    Article  ADS  CAS  Google Scholar 

  10. Jing, S.et al. GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-α, a novel receptor for GDNR. Cell 85, 1113–1124 (1996).

    Article  CAS  Google Scholar 

  11. Trupp, M.et al. Functional receptor for GDNF encoded by the c-ret proto-oncogene. Nature 381, 785–789 (1996).

    Article  ADS  CAS  Google Scholar 

  12. Durbec, P.et al. GDNF signalling through the Ret receptor tyrosine kinase. Nature 381, 789–793 (1996).

    Article  ADS  CAS  Google Scholar 

  13. Vega, Q. C., Worby, C. A., Lechner, M. S., Dixon, J. E. & Dressler, G. R. Glial cell line-derived neurotrophic factor activates the receptor tyrosine kinase RET and promotes kidney morphogenesis. Proc. Natl Acad. Sci. USA 93, 10657–10661 (1996).

    Article  ADS  CAS  Google Scholar 

  14. Gerber, L. D., Kodukula, K. & Udenfried, S. Phosphatidylinositol glycan (PI-G) anchored membrane proteins. Amino acid requirements adjacent to the site of cleavage and PI-G attachment in the COOH-terminal signal peptide. J. Biol. Chem. 267, 12168–12173 (1992).

    CAS  PubMed  Google Scholar 

  15. Davis, S.et al. LIFRβ and gp130 as heterodimerizing signal transducers of the tripartite CNTF receptor. Science 260, 1805–1808 (1993).

    Article  ADS  CAS  Google Scholar 

  16. Koke, J. A., Yang, M., Henner, D. J., Volwerk, J. J. & Griffin, O. H. High-level expression in Escherichia coli and rapid purification of phosphatidylinositol-specific phospholipase C from Bacillus cereus and Bacillus thuringiensis. Protein Expr. Purif. 2, 51–58 (1991).

    Article  CAS  Google Scholar 

  17. Klein, R.et al. The trkB tyrosine protein kinase is a receptor for brain-derived neurotrophic factor and neurotrophin-3. Cell 66, 395–403 (1991).

    Article  CAS  Google Scholar 

  18. Klein, R. D.et al. AGPI-linked protein that interacts with Ret to form a candidate neurturin receptor. Nature 387, 717–721 (1997).

    Article  ADS  CAS  Google Scholar 

  19. Lee, J. D.et al. Glycosyl-phosphatidylinositol-anchored or integral membrane forms of CD14 mediate identical cellular responses to endotoxin. Proc. Natl Acad. Sci. YSA 90, 9930–9934 (1993).

    Article  ADS  CAS  Google Scholar 

  20. Pugin, J.et al. Lipopolysaccharide activation of human endothelial and epithelial cells is mediated by lipopolysaccharide-binding protein and soluble CD14. Proc. Natl Acad. Sci. USA 90, 2744–2747 (1993).

    Article  ADS  CAS  Google Scholar 

  21. Baka, I. D.et al. Intracellular compartmentalisation of two differently spliced S-REX/NSP mRNAs in neurons. Mol. Cell Neurosci. 7, 289–303 (1996).

    Article  CAS  Google Scholar 

  22. Ninkina, N.et al. Expression and function of TrkB variants in developing sensory neurons. EMBO J. 15, 6385–6393 (1996).

    Article  CAS  Google Scholar 

  23. Davies, A. M., Minichiello, L. & Klein, R. Developmental changes in NT3 signalling via TrkA and TrkB in embryonic neurons. EMBO J. 14, 4482–4489 (1995).

    Article  CAS  Google Scholar 

  24. Allsopp, T. E., Wyatt, S., Paterson, H. F. & Davies, A. M. The proto-oncogene bcl-2 can selectively rescue neurotrophic factor-dependent neurons from apoptosis. Cell 73, 295–306 (1993).

    Article  CAS  Google Scholar 

  25. Buj-Bello, A., Pinon, L. G. & Davies, A. M. The survival of NGF-dependent but not BDNF-dependent cranial sensory neurons is promoted by several different neurotrophins early in their development. Development 120, 1573–1580 (1994).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank H. Philips, R. Klein, R. Vandlen, B. Moffet and L. Simmons for the purified recombinant GDNF and neurturin; J. Winslow and G. Burdon for the purified recombinant BDNF; and D. Roche and J. Allan for preparing the illustrations. This work was supported by Action Research and the Wellcome Trust.

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Author notes

  1. Miguel Chinchetru

    Present address: Departmento de Bioquimica y Biologia Molecular, Facultad de Veterinaria, Universidad de León, 24007, León, Spain

  2. Anna Buj-Bello and Jimi Adu: These authors contributed equally to this work.

Authors and Affiliations

  1. *School of Biological and Medical Sciences, Bute Medical Buildings, University of St Andrews, St Andrews, KY16 9AT, Fife, UK

    Anna Buj-Bello, Jimi Adu, Luzia G. P. Piñón, Antony Horton, Jane Thompson, Vladimir L. Buchman & Alun M. Davies

  2. †Department of Neuroscience, Genentech, Inc., 460 Point San Bruno Boulevard, South San Francisco, 94080, California, USA

    Arnon Rosenthal

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Correspondence to Alun M. Davies.

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Buj-Bello, A., Adu, J., Piñón, L. et al. Neurturin responsiveness requires a GPI-linked receptor and the Ret receptor tyrosine kinase. Nature 387, 721–724 (1997). https://doi.org/10.1038/42729

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