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

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.

• Authors: 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 Perlmann
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 6 Pg. 2360-5 (Feb 05 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 23341612 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nr4a2 protein, mouse
• Nuclear Receptor Subfamily 4, Group A, Member 2
• Dopamine

Topics

• Animals
• Behavior, Animal
• Cell Nucleus (genetics)
• Dopamine (metabolism)
• Dopaminergic Neurons (metabolism, ultrastructure)
• Gene Expression
• Genes, Mitochondrial
• Mice
• Mice, Knockout
• Mice, Transgenic
• Nuclear Receptor Subfamily 4, Group A, Member 2 (deficiency, genetics, metabolism)
• Visual Cortex (metabolism)