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Otx2 controls neuron subtype identity in ventral tegmental area and antagonizes vulnerability to MPTP

Nature Neuroscience volume 13, pages 1481–1488 (2010)Cite this article

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Abstract

Mesencephalic-diencephalic dopaminergic neurons control locomotor activity and emotion and are affected in neurodegenerative and psychiatric diseases. The homeoprotein Otx2 is restricted to ventral tegmental area (VTA) neurons that are prevalently complementary to those expressing Girk2 and glycosylated active form of the dopamine transporter (Dat). High levels of glycosylated Dat mark neurons with efficient dopamine uptake and pronounced vulnerability to Parkinsonian degeneration. We found that Otx2 controls neuron subtype identity by antagonizing molecular and functional features of dorsal-lateral VTA, such as Girk2 and Dat expression. Otx2 limited the number of VTA neurons with efficient dopamine uptake and conferred resistance to the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-HCl (MPTP) neurotoxin. Ectopic Otx2 expression also provided neurons of the substantia nigra with efficient neuroprotection to MPTP. These findings indicate that Otx2 is required to specify neuron subtype identity in VTA and may antagonize vulnerability to the Parkinsonian toxin MPTP.

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Figure 1: Otx2 postmitotic inactivation and overexpression.
Figure 2: Otx2 inactivation does not affect the survival of Otx2-positive VTA neurons but induces an increase in the number of GFP and Girk2 double-positive neurons.
Figure 3: Otx2 activation in the VTA generates a reduction in the number of Girk2-positive neurons.
Figure 4: The level and expression profile of glyco-Dat are altered in Otx2 mutants.
Figure 5: Otx2 negatively controls Dat mRNA expression.
Figure 6: Otx2 is a neuroprotective factor for the Otx2-positive VTA neurons and this property may be conferred to SNpc neurons.

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Acknowledgements

The authors would like to thank D. Grieco and T. Russo for helpful discussions and criticisms on the manuscript, S. Casola for the R26 targeting vector, G. Corte for the Otx2 antibody and the staff of the CEINGE animal house for excellent animal care. We are grateful to E. Bricola for typing the manuscript. This work was supported by the FP7 for the project mdDA NEURODEV (222999) to A.S. and W.W., the FP6 project for the EUTRACC Integrated Project (LSHG-CT-2007-037445) to A.S. and W.W., the 'Stem Cell Project' of Fondazione Roma and the Italian Association for Cancer Research to A.S., and the Federal Ministry of Education and Research in the framework of the National Genome Research Network (NGFN+ Functional Genomics of Parkinson Disease FKZ 01GS08174) to W.W.

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Author notes

  1. Michela Di Salvio and Luca Giovanni Di Giovannantonio: These authors contributed equally to this work.

Authors and Affiliations

  1. CEINGE Biotecnologie Avanzate, Naples, Italy

    Michela Di Salvio, Luca Giovanni Di Giovannantonio, Dario Acampora, Daniela Omodei & Antonio Simeone

  2. SEMM European School of Molecular Medicine, Naples site, Naples, Italy

    Dario Acampora & Antonio Simeone

  3. Institute of Genetics and Biophysics “A. Buzzati-Traverso,” CNR, Naples, Italy

    Dario Acampora & Antonio Simeone

  4. Dipartimento di Matematica e Statistica, Università degli Studi del Sannio, Benevento, Italy

    Raffaele Prosperi

  5. Helmholtz Zentrum München, Technische Universität München, Deutsches Zentrum für Neurodegnerative Erkrankungen München, Institute of Developmental Genetics, Munich/Neuherberg, Germany

    Nilima Prakash & Wolfgang Wurst

  6. Max Planck Institute of Psychiatry, Molecular Neurogenetics, Munich, Germany

    Nilima Prakash & Wolfgang Wurst

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Contributions

M.D.S. and L.G.D.G. performed the experiments, D.A. generated the Otx2 mutant mice, R.P. performed the statistical analysis, D.O. and N.P. contributed to the phenotypic analysis, W.W. contributed to the interpretation of results and the writing of the manuscript, and A.S. designed and interpreted the experiments and wrote the manuscript.

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Correspondence to Antonio Simeone.

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Di Salvio, M., Di Giovannantonio, L., Acampora, D. et al. Otx2 controls neuron subtype identity in ventral tegmental area and antagonizes vulnerability to MPTP. Nat Neurosci 13, 1481–1488 (2010). https://doi.org/10.1038/nn.2661

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