Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Absolute requirement of GDNF for adult catecholaminergic neuron survival

Nature Neuroscience volume 11, pages 755–761 (2008)Cite this article

Abstract

GDNF is a potent neurotrophic factor that protects catecholaminergic neurons from toxic damage and induces fiber outgrowth. However, the actual role of endogenous GDNF in the normal adult brain is unknown, even though GDNF-based therapies are considered promising for neurodegenerative disorders. We have generated a conditional GDNF-null mouse to suppress GDNF expression in adulthood, hence avoiding the developmental compensatory modifications masking its true physiologic action. After Gdnf ablation, mice showed a progressive hypokinesia and a selective decrease of brain tyrosine hydroxylase (Th) mRNA, accompanied by pronounced catecholaminergic cell death, affecting most notably the locus coeruleus, which practically disappears; the substantia nigra; and the ventral tegmental area. These data unequivocally demonstrate that GDNF is indispensable for adult catecholaminergic neuron survival and also show that, under physiologic conditions, downregulation of a single trophic factor can produce massive neuronal death.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Molecular characterization of the conditional Gdnf knockout mice.
Figure 2: Mesencephalic dopaminergic neuronal death after Gdnf ablation in adult mice.
Figure 3: Locus coeruleus noradrenergic neuronal death after Gdnf ablation in adult mouse.
Figure 4: Peripheral and hypothalamic dopaminergic cell survival in conditional GDNF knockout mice.
Figure 5: Behavioral analysis of adult GDNF-depleted mice.

Similar content being viewed by others

References

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

    Article  CAS  Google Scholar 

  2. Kirik, D., Georgievska, B. & Bjorklund, A. Localized striatal delivery of GDNF as a treatment for Parkinson disease. Nat. Neurosci. 7, 105–110 (2004).

    Article  CAS  Google Scholar 

  3. Akerud, P., Canals, J.M., Snyder, E.Y. & Arenas, E. Neuroprotection through delivery of glial cell line-derived neurotrophic factor by neural stem cells in a mouse model of Parkinson's disease. J. Neurosci. 21, 8108–8118 (2001).

    Article  CAS  Google Scholar 

  4. Choi-Lundberg, D.L. et al. Dopaminergic neurons protected from degeneration by GDNF gene therapy. Science 275, 838–841 (1997).

    Article  CAS  Google Scholar 

  5. Gash, D.M. et al. Functional recovery in parkinsonian monkeys treated with GDNF. Nature 380, 252–255 (1996).

    Article  CAS  Google Scholar 

  6. Kordower, J.H. et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. Science 290, 767–773 (2000).

    Article  CAS  Google Scholar 

  7. Rosenblad, C., Martinez-Serrano, A. & Bjorklund, A. Intrastriatal glial cell line-derived neurotrophic factor promotes sprouting of spared nigrostriatal dopaminergic afferents and induces recovery of function in a rat model of Parkinson's disease. Neuroscience 82, 129–137 (1998).

    Article  CAS  Google Scholar 

  8. Tomac, A. et al. Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature 373, 335–339 (1995).

    Article  CAS  Google Scholar 

  9. Arenas, E., Trupp, M., Akerud, P. & Ibanez, C.F. GDNF prevents degeneration and promotes the phenotype of brain noradrenergic neurons in vivo. Neuron 15, 1465–1473 (1995).

    Article  CAS  Google Scholar 

  10. Gill, S.S. et al. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat. Med. 9, 589–595 (2003).

    Article  CAS  Google Scholar 

  11. Slevin, J.T. et al. Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputaminal infusion of glial cell line-derived neurotrophic factor. J. Neurosurg. 102, 216–222 (2005).

    Article  CAS  Google Scholar 

  12. Lang, A.E. et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann. Neurol. 59, 459–466 (2006).

    Article  CAS  Google Scholar 

  13. Check, E. Second chance. Nat. Med. 13, 770–771 (2007).

    Article  CAS  Google Scholar 

  14. Trupp, M., Belluardo, N., Funakoshi, H. & Ibanez, C.F. Complementary and overlapping expression of glial cell line-derived neurotrophic factor (GDNF), c-ret proto-oncogene, and GDNF receptor-alpha indicates multiple mechanisms of trophic actions in the adult rat CNS. J. Neurosci. 17, 3554–3567 (1997).

    Article  CAS  Google Scholar 

  15. Toledo-Aral, J.J., Mendez-Ferrer, S., Pardal, R., Echevarria, M. & Lopez-Barneo, J. Trophic restoration of the nigrostriatal dopaminergic pathway in long-term carotid body-grafted parkinsonian rats. J. Neurosci. 23, 141–148 (2003).

    Article  CAS  Google Scholar 

  16. Villadiego, J. et al. Selective glial cell line-derived neurotrophic factor production in adult dopaminergic carotid body cells in situ and after intrastriatal transplantation. J. Neurosci. 25, 4091–4098 (2005).

    Article  CAS  Google Scholar 

  17. Arjona, V. et al. Autotransplantation of human carotid body cell aggregates for treatment of Parkinson's disease. Neurosurgery 53, 321–328 discussion 328–330 (2003).

    Article  Google Scholar 

  18. Espejo, E.F., Montoro, R.J., Armengol, J.A. & Lopez-Barneo, J. Cellular and functional recovery of Parkinsonian rats after intrastriatal transplantation of carotid body cell aggregates. Neuron 20, 197–206 (1998).

    Article  CAS  Google Scholar 

  19. Minguez-Castellanos, A. et al. Carotid body autotransplantation in Parkinson disease: A clinical and PET study. J. Neurol. Neurosurg. Psychiatry 78, 825–831 (2007).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  23. Boger, H.A. et al. A partial GDNF depletion leads to earlier age-related deterioration of motor function and tyrosine hydroxylase expression in the substantia nigra. Exp. Neurol. 202, 336–347 (2006).

    Article  CAS  Google Scholar 

  24. Boger, H.A. et al. Long-term consequences of methamphetamine exposure in young adults are exacerbated in glial cell line-derived neurotrophic factor heterozygous mice. J. Neurosci. 27, 8816–8825 (2007).

    Article  CAS  Google Scholar 

  25. Jain, S. et al. RET is dispensable for maintenance of midbrain dopaminergic neurons in adult mice. J. Neurosci. 26, 11230–11238 (2006).

    Article  CAS  Google Scholar 

  26. Kramer, E.R. et al. Absence of Ret signaling in mice causes progressive and late degeneration of the nigrostriatal system. PLoS Biol. 5, e39 (2007).

    Article  Google Scholar 

  27. Hayashi, S. & McMahon, A.P. Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. Dev. Biol. 244, 305–318 (2002).

    Article  CAS  Google Scholar 

  28. Bjorklund, A. & Hokfelt, T. Handbook of Chemical Neuroanatomy: Classical Neurotransmitters in the CNS part I, 123–156 (Elsevier, Amsterdam, 1984).

    Google Scholar 

  29. Lindvall, O. & Stenevi, U. Dopamine and noradrenaline neurons projecting to the septal area in the rat. Cell Tissue Res. 190, 383–407 (1978).

    Article  CAS  Google Scholar 

  30. Galarza, M. Evidence of the subcommissural organ in humans and its association with hydrocephalus. Neurosurg. Rev. 25, 205–215 (2002).

    Article  Google Scholar 

  31. Fleming, S.M. et al. Early and progressive sensorimotor anomalies in mice overexpressing wild-type human alpha-synuclein. J. Neurosci. 24, 9434–9440 (2004).

    Article  CAS  Google Scholar 

  32. Meredith, G.E. & Kang, U.J. Behavioral models of Parkinson's disease in rodents: a new look at an old problem. Mov. Disord. 21, 1595–1606 (2006).

    Article  Google Scholar 

  33. Sedelis, M., Schwarting, R.K. & Huston, J.P. Behavioral phenotyping of the MPTP mouse model of Parkinson's disease. Behav. Brain Res. 125, 109–125 (2001).

    Article  CAS  Google Scholar 

  34. Zhou, Q.Y. & Palmiter, R.D. Dopamine-deficient mice are severely hypoactive, adipsic, and aphagic. Cell 83, 1197–1209 (1995).

    Article  CAS  Google Scholar 

  35. Granholm, A.C. et al. Glial cell line-derived neurotrophic factor is essential for postnatal survival of midbrain dopamine neurons. J. Neurosci. 20, 3182–3190 (2000).

    Article  CAS  Google Scholar 

  36. Paratcha, G., Ledda, F. & Ibanez, C.F. The neural cell adhesion molecule NCAM is an alternative signaling receptor for GDNF family ligands. Cell 113, 867–879 (2003).

    Article  CAS  Google Scholar 

  37. Chao, C.C., Ma, Y.L., Chu, K.Y. & Lee, E.H. Integrin αv and NCAM mediate the effects of GDNF on DA neuron survival, outgrowth, DA turnover and motor activity in rats. Neurobiol. Aging 24, 105–116 (2003).

    Article  CAS  Google Scholar 

  38. Tome, M. et al. The subcommissural organ expresses D2, D3, D4, and D5 dopamine receptors. Cell Tissue Res. 317, 65–77 (2004).

    Article  CAS  Google Scholar 

  39. Zarow, C., Lyness, S.A., Mortimer, J.A. & Chui, H.C. Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch. Neurol. 60, 337–341 (2003).

    Article  Google Scholar 

  40. Matzuk, M.M. & Saper, C.B. Preservation of hypothalamic dopaminergic neurons in Parkinson's disease. Ann. Neurol. 18, 552–555 (1985).

    Article  CAS  Google Scholar 

  41. Srinivasan, J. & Schmidt, W.J. Potentiation of parkinsonian symptoms by depletion of locus coeruleus noradrenaline in 6-hydroxydopamine-induced partial degeneration of substantia nigra in rats. Eur. J. Neurosci. 17, 2586–2592 (2003).

    Article  CAS  Google Scholar 

  42. Guo, C., Yang, W. & Lobe, C.G. A Cre recombinase transgene with mosaic, widespread tamoxifen-inducible action. Genesis 32, 8–18 (2002).

    Article  CAS  Google Scholar 

  43. Mejias, R. et al. Neuroprotection by transgenic expression of glucose-6-phosphate dehydrogenase in dopaminergic nigrostriatal neurons of mice. J. Neurosci. 26, 4500–4508 (2006).

    Article  CAS  Google Scholar 

  44. Franklin, B.J. & Paxinos, G.T. The Mouse Brain in Stereotaxic Coordinates (Academic, New York, 1996).

    Google Scholar 

Download references

Acknowledgements

We wish to thank R. Pardal, M. Patterson and J.J. Toledo-Aral for comments on the manuscript and J. Sanchez García for karyotyping of ES cells. Support was obtained from the Juan March Foundation, the Marcelino Botín Foundation, the Spanish Ministry of Science and Education, the Spanish Ministry of Health (TERCEL) and the Andalusian Government. CIBERNED is funded by the Instituto de Salud Carlos III.

Author information

Author notes

  1. Alberto Pascual and María Hidalgo-Figueroa: These authors contributed equally to this work.

Authors and Affiliations

  1. Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avenida Manuel Siurot s/n, Sevilla, 41013, Spain

    Alberto Pascual, María Hidalgo-Figueroa, José I Piruat, C Oscar Pintado, Raquel Gómez-Díaz & José López-Barneo

  2. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain

    Alberto Pascual, José I Piruat, Raquel Gómez-Díaz & José López-Barneo

Authors
  1. Alberto Pascual
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. María Hidalgo-Figueroa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. José I Piruat
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Oscar Pintado
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Raquel Gómez-Díaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. José López-Barneo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.P. and M.H.-F. designed and conducted most of the experiments. A.P., C.O.P., R.G.-D. and J.I.P. generated the GDNF conditional knockout mice. J.L.-B. supervised the project. A.P. and J.L.-B. wrote the manuscript.

Corresponding author

Correspondence to José López-Barneo.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1, 2 and Supplementary Table 1 (PDF 1641 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pascual, A., Hidalgo-Figueroa, M., Piruat, J. et al. Absolute requirement of GDNF for adult catecholaminergic neuron survival. Nat Neurosci 11, 755–761 (2008). https://doi.org/10.1038/nn.2136

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.2136

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing