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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.

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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.

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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.

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  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

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  1. Alberto Pascual
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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.

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Correspondence to José López-Barneo.

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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

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