title: 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: Ludwig Institute for Cancer Research Ltd, Stockholm Branch, SE-17177 Stockholm,  Sweden.
authors: Banafsheh
authors: B
authors: Kadkhodaei
authors: Alexandra
authors: A
authors: Alvarsson
authors: Nicoletta
authors: N
authors: Schintu
authors: Daniel
authors: D
authors: Ramsköld
authors: Nikolaos
authors: N
authors: Volakakis
authors: Eliza
authors: E
authors: Joodmardi
authors: Takashi
authors: T
authors: Yoshitake
authors: Jan
authors: J
authors: Kehr
authors: Mickael
authors: M
authors: Decressac
authors: Anders
authors: A
authors: Björklund
authors: Rickard
authors: R
authors: Sandberg
authors: Per
authors: P
authors: Svenningsson
authors: Thomas
authors: T
authors: Perlmann
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002467:Cell Nucleus / Q000235:genetics; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000648:ultrastructure; D015870:Gene Expression; D050259:Genes, Mitochondrial; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014793:Visual Cortex / Q000378:metabolism
chemical_list: C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D004298:Dopamine