Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons

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

Research output: Contribution to journalArticle

202 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)15923-15932
Number of pages10
JournalJournal of Neuroscience
Volume29
Issue number50
DOIs
Publication statusPublished - 16-12-2009

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Dopaminergic Neurons
Mesencephalon
Maintenance
Corpus Striatum
Transcription Factors
Neurons
Parkinson Disease
Brain
Nerve Degeneration
Dependovirus
Dopamine Plasma Membrane Transport Proteins
Ventral Tegmental Area
Gene Targeting
Rare Diseases
Neurodegenerative Diseases
Embryonic Development
Mutation
Genes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Kadkhodaei, B., Ito, T., Joodmardi, E., Mattsson, B., Rouillard, C., Carta, M., ... Perlmann, T. (2009). Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons. Journal of Neuroscience, 29(50), 15923-15932. https://doi.org/10.1523/JNEUROSCI.3910-09.2009
Kadkhodaei, Banafsheh ; Ito, Takehito ; Joodmardi, Eliza ; Mattsson, Bengt ; Rouillard, Claude ; Carta, Manolo ; Muramatsu, Shin Ichi ; Ichinose, Chiho ; Nomura, Takahide ; Metzger, Daniel ; Chambon, Pierre ; Lindqvist, Eva ; Larsson, Nils Göran ; Olson, Lars ; Björklund, Anders ; Ichinose, Hiroshi ; Perlmann, Thomas. / Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons. In: Journal of Neuroscience. 2009 ; Vol. 29, No. 50. pp. 15923-15932.
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Kadkhodaei, B, Ito, T, Joodmardi, E, Mattsson, B, Rouillard, C, Carta, M, Muramatsu, SI, Ichinose, C, Nomura, T, Metzger, D, Chambon, P, Lindqvist, E, Larsson, NG, Olson, L, Björklund, A, Ichinose, H & Perlmann, T 2009, 'Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons', Journal of Neuroscience, vol. 29, no. 50, pp. 15923-15932. https://doi.org/10.1523/JNEUROSCI.3910-09.2009

Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons. / Kadkhodaei, Banafsheh; Ito, Takehito; Joodmardi, Eliza; Mattsson, Bengt; Rouillard, Claude; Carta, Manolo; Muramatsu, Shin Ichi; Ichinose, Chiho; Nomura, Takahide; Metzger, Daniel; Chambon, Pierre; Lindqvist, Eva; Larsson, Nils Göran; Olson, Lars; Björklund, Anders; Ichinose, Hiroshi; Perlmann, Thomas.

In: Journal of Neuroscience, Vol. 29, No. 50, 16.12.2009, p. 15923-15932.

Research output: Contribution to journalArticle

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AU - Ito, Takehito

AU - Joodmardi, Eliza

AU - Mattsson, Bengt

AU - Rouillard, Claude

AU - Carta, Manolo

AU - Muramatsu, Shin Ichi

AU - Ichinose, Chiho

AU - Nomura, Takahide

AU - Metzger, Daniel

AU - Chambon, Pierre

AU - Lindqvist, Eva

AU - Larsson, Nils Göran

AU - Olson, Lars

AU - Björklund, Anders

AU - Ichinose, Hiroshi

AU - Perlmann, Thomas

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N2 - 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.

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Kadkhodaei B, Ito T, Joodmardi E, Mattsson B, Rouillard C, Carta M et al. Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons. Journal of Neuroscience. 2009 Dec 16;29(50):15923-15932. https://doi.org/10.1523/JNEUROSCI.3910-09.2009