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The Role of Otx2 in Adult Mesencephalic–Diencephalic Dopaminergic Neurons

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Abstract

Mesencephalic and diencephalic dopaminergic (mdDA) progenitors generate two major groups of neurons corresponding to the A9 neurons of the substantia nigra pars compacta (SNpc) and the A10 neurons of the ventral tegmental area (VTA). MdDA neurons control motor, sensorimotor and motivated behaviour and their degeneration or abnormal functioning is associated to Parkinson’s disease and psychiatric disorders. Although relevant advances have been made, the molecular basis controlling identity, survival and vulnerability to neurodegeneration of SNpc and VTA neurons remains poorly understood. Here, we will review recent findings on the role exerted by the transcription factor Otx2 in adult mdDA neurons. Otx2 expression is restricted to a relevant fraction of VTA neurons and absent in the SNpc. In particular, Otx2 is prevalently excluded from neurons of the dorsal–lateral VTA, which expressed Girk2 and high level of the dopamine transporter (Dat). Loss and gain of function mouse models revealed that Otx2 controls neuron subtype identity by antagonizing molecular and functional features of the dorsal–lateral VTA such as Girk2 and Dat expression as well as vulnerability to the parkinsonian MPTP toxin. Furthermore, when ectopically expressed in the SNpc, Otx2 suppresses Dat expression and confers efficient neuroprotection to MPTP toxicity by suppressing efficient DA uptake.

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Acknowledgments

The experiments and findings here discussed have been supported by the FP7 for the project mdDA NEURODEV (222999), the FP6 project for the EUTRACC Integrated Project (LSHG-CT-2007-037445), the “Stem Cell Project” of Fondazione Roma, and the Italian Association for Cancer Research (AIRC) and the MIUR for the PRIN project (20079ZLWYP_003).

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  1. CEINGE Biotecnologie Avanzate, and SEMM European School of Molecular Medicine, Via Comunale Margherita 482, 80145, Naples, Italy

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

  2. Institute of Genetics and Biophysics “A. Buzzati-Traverso”, CNR, Via P. Castellino 111, 80131, Naples, Italy

    Antonio Simeone & Dario Acampora

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  1. Antonio Simeone
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  2. Michela Di Salvio
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  3. Luca Giovanni Di Giovannantonio
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Correspondence to Antonio Simeone.

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Simeone, A., Di Salvio, M., Di Giovannantonio, L.G. et al. The Role of Otx2 in Adult Mesencephalic–Diencephalic Dopaminergic Neurons. Mol Neurobiol 43, 107–113 (2011). https://doi.org/10.1007/s12035-010-8148-y

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