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

Nat Neurosci. 2010 Dec;13(12):1481-8. doi: 10.1038/nn.2661. Epub 2010 Nov 7.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / pathology
  • Embryonic Stem Cells / physiology
  • MPTP Poisoning / metabolism
  • MPTP Poisoning / pathology
  • MPTP Poisoning / prevention & control*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Transgenic
  • Neurons / classification*
  • Neurons / pathology
  • Neurons / physiology*
  • Otx Transcription Factors / physiology*
  • Ventral Tegmental Area / cytology*
  • Ventral Tegmental Area / pathology
  • Ventral Tegmental Area / physiology*


  • Otx Transcription Factors
  • Otx2 protein, mouse