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Transcription factor Nurr1 maintains fiber integrity and nuclear-encoded mitochondrial gene expression in dopamine neurons

Kadkhodaei, Banafsheh; Alvarsson, Alexandra; Schintu, Nicoletta; Ramskold, Daniel; Volakakis, Nikolaos; Joodmardi, Eliza; Yoshitake, Takashi; Kehr, Jan; Decressac, Mickael LU and Björklund, Anders LU , et al. (2013) In Proceedings of the National Academy of Sciences 110(6). p.2360-2365
Abstract
Developmental transcription factors important in early neuron specification and differentiation often remain expressed in the adult brain. However, how these transcription factors function to mantain appropriate neuronal identities in adult neurons and how transcription factor dysregulation may contribute to disease remain largely unknown. The transcription factor Nurr1 has been associated with Parkinson's disease and is essential for the development of ventral midbrain dopamine (DA) neurons. We used conditional Nurr1 gene-targeted mice in which Nurr1 is ablated selectively in mature DA neurons by treatment with tamoxifen. We show that Nurr1 ablation results in a progressive pathology associated with reduced striatal DA, impaired motor... (More)
Developmental transcription factors important in early neuron specification and differentiation often remain expressed in the adult brain. However, how these transcription factors function to mantain appropriate neuronal identities in adult neurons and how transcription factor dysregulation may contribute to disease remain largely unknown. The transcription factor Nurr1 has been associated with Parkinson's disease and is essential for the development of ventral midbrain dopamine (DA) neurons. We used conditional Nurr1 gene-targeted mice in which Nurr1 is ablated selectively in mature DA neurons by treatment with tamoxifen. We show that Nurr1 ablation results in a progressive pathology associated with reduced striatal DA, impaired motor behaviors, and dystrophic axons and dendrites. We used laser-microdissected DA neurons for RNA extraction and next-generation mRNA sequencing to identify Nurr1-regulated genes. This analysis revealed that Nurr1 functions mainly in transcriptional activation to regulate a battery of genes expressed in DA neurons. Importantly, nuclear-encoded mitochondrial genes were identified as the major functional category of Nurr1-regulated target genes. These studies indicate that Nurr1 has a key function in sustaining high respiratory function in these cells, and that Nurr1 ablation in mice recapitulates early features of Parkinson's disease. (Less)
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keywords
NR4A2, nuclear receptor, laser capture microdissection, RNA sequencing, orphan receptor
in
Proceedings of the National Academy of Sciences
volume
110
issue
6
pages
2360 - 2365
publisher
National Acad Sciences
external identifiers
  • wos:000315209800080
  • scopus:84873423314
ISSN
1091-6490
DOI
10.1073/pnas.1221077110
language
English
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yes
id
40ab73ed-223e-4f27-baca-d8b724416fdd (old id 3674517)
date added to LUP
2013-05-02 08:58:19
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2019-03-05 01:29:47
@article{40ab73ed-223e-4f27-baca-d8b724416fdd,
  abstract     = {Developmental transcription factors important in early neuron specification and differentiation often remain expressed in the adult brain. However, how these transcription factors function to mantain appropriate neuronal identities in adult neurons and how transcription factor dysregulation may contribute to disease remain largely unknown. The transcription factor Nurr1 has been associated with Parkinson's disease and is essential for the development of ventral midbrain dopamine (DA) neurons. We used conditional Nurr1 gene-targeted mice in which Nurr1 is ablated selectively in mature DA neurons by treatment with tamoxifen. We show that Nurr1 ablation results in a progressive pathology associated with reduced striatal DA, impaired motor behaviors, and dystrophic axons and dendrites. We used laser-microdissected DA neurons for RNA extraction and next-generation mRNA sequencing to identify Nurr1-regulated genes. This analysis revealed that Nurr1 functions mainly in transcriptional activation to regulate a battery of genes expressed in DA neurons. Importantly, nuclear-encoded mitochondrial genes were identified as the major functional category of Nurr1-regulated target genes. These studies indicate that Nurr1 has a key function in sustaining high respiratory function in these cells, and that Nurr1 ablation in mice recapitulates early features of Parkinson's disease.},
  author       = {Kadkhodaei, Banafsheh and Alvarsson, Alexandra and Schintu, Nicoletta and Ramskold, Daniel and Volakakis, Nikolaos and Joodmardi, Eliza and Yoshitake, Takashi and Kehr, Jan and Decressac, Mickael and Björklund, Anders and Sandberg, Rickard and Svenningsson, Per and Perlmann, Thomas},
  issn         = {1091-6490},
  keyword      = {NR4A2,nuclear receptor,laser capture microdissection,RNA sequencing,orphan receptor},
  language     = {eng},
  number       = {6},
  pages        = {2360--2365},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Transcription factor Nurr1 maintains fiber integrity and nuclear-encoded mitochondrial gene expression in dopamine neurons},
  url          = {http://dx.doi.org/10.1073/pnas.1221077110},
  volume       = {110},
  year         = {2013},
}