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Nurr1 Is Required for Maintenance of Maturing and Adult Midbrain Dopamine Neurons

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Author

  • Banafsheh Kadkhodaei
  • Takehito Ito
  • Eliza Joodmardi
  • Bengt Mattsson
  • Claude Rouillard
  • Manolo Carta
  • Shin-Ichi Muramatsu
  • Chiho Sumi-Ichinose
  • Takahide Nomura
  • Daniel Metzger
  • Pierre Chambon
  • Eva Lindqvist
  • Nils-Goeran Larsson
  • Lars Olson
  • Anders Björklund
  • Hiroshi Ichinose
  • Thomas Perlmann
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Summary, in English

Transcription factors involved in the specification and differentiation of neurons often continue to be expressed in the adult brain, but remarkably little is known about their late functions. Nurr1, one such transcription factor, is essential for early differentiation of midbrain dopamine (mDA) neurons but continues to be expressed into adulthood. In Parkinson's disease, Nurr1 expression is diminished and mutations in the Nurr1 gene have been identified in rare cases of disease; however, the significance of these observations remains unclear. Here, a mouse strain for conditional targeting of the Nurr1 gene was generated, and Nurr1 was ablated either at late stages of mDA neuron development by crossing with mice carrying Cre under control of the dopamine transporter locus or in the adult brain by transduction of adeno-associated virus Cre-encoding vectors. Nurr1 deficiency in maturing mDA neurons resulted in rapid loss of striatal DA, loss of mDA neuron markers, and neuron degeneration. In contrast, a more slowly progressing loss of striatal DA and mDA neuron markers was observed after ablation in the adult brain. As in Parkinson's disease, neurons of the substantia nigra compacta were more vulnerable than cells in the ventral tegmental area when Nurr1 was ablated at late embryogenesis. The results show that developmental pathways play key roles for the maintenance of terminally differentiated neurons and suggest that disrupted function of Nurr1 and other developmental transcription factors may contribute to neurodegenerative disease.

Publishing year

2009

Language

English

Pages

15923-15932

Publication/Series

Journal of Neuroscience

Volume

29

Issue

50

Document type

Journal article

Publisher

Society for Neuroscience

Topic

  • Neurosciences

Status

Published

Research group

  • Neurobiology

ISBN/ISSN/Other

  • ISSN: 1529-2401