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

Banafsheh Kadkhodaei, Alexandra Alvarsson, Nicoletta Schintu, Daniel Ramsköld, Nikolaos Volakakis, Eliza Joodmardi, Takashi Yoshitake, Jan Kehr, Mickael Decressac, Anders Björklund, Rickard Sandberg, Per Svenningsson, Thomas Perlmanna

Research output: Contribution to journalArticlepeer-review

132 Scopus citations

Abstract

Developmental transcription factors important in early neuron specification and differentiation often remain expressed in the adult brain. However, howthese transcription factors function tomantain 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 genetargeted 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.

Original languageEnglish
Pages (from-to)2360-2365
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number6
DOIs
StatePublished - 5 Feb 2013
Externally publishedYes

Keywords

  • Laser capture microdissection
  • NR4A2
  • Nuclear receptor
  • Orphan receptor
  • RNA sequencing

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