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

Kadkhodaei, Banafsheh; Ito, Takehito; Joodmardi, Eliza; Mattsson, Bengt LU ; Rouillard, Claude; Carta, Manolo LU ; Muramatsu, Shin-Ichi; Sumi-Ichinose, Chiho; Nomura, Takahide and Metzger, Daniel, et al. (2009) In Journal of Neuroscience 29(50). p.15923-15932
Abstract
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... (More)
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. (Less)
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Journal of Neuroscience
volume
29
issue
50
pages
15923 - 15932
publisher
Society for Neuroscience
external identifiers
  • wos:000272837000034
  • scopus:72449191782
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.3910-09.2009
language
English
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yes
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07c0e6b9-31b9-42e2-81e6-4b124fee5478 (old id 1532277)
date added to LUP
2010-01-29 12:42:50
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@article{07c0e6b9-31b9-42e2-81e6-4b124fee5478,
  abstract     = {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.},
  author       = {Kadkhodaei, Banafsheh and Ito, Takehito and Joodmardi, Eliza and Mattsson, Bengt and Rouillard, Claude and Carta, Manolo and Muramatsu, Shin-Ichi and Sumi-Ichinose, Chiho and Nomura, Takahide and Metzger, Daniel and Chambon, Pierre and Lindqvist, Eva and Larsson, Nils-Goeran and Olson, Lars and Björklund, Anders and Ichinose, Hiroshi and Perlmann, Thomas},
  issn         = {1529-2401},
  language     = {eng},
  number       = {50},
  pages        = {15923--15932},
  publisher    = {Society for Neuroscience},
  series       = {Journal of Neuroscience},
  title        = {Nurr1 Is Required for Maintenance of Maturing and Adult Midbrain Dopamine Neurons},
  url          = {http://dx.doi.org/10.1523/JNEUROSCI.3910-09.2009},
  volume       = {29},
  year         = {2009},
}