title: Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons.
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.
authors.affiliation: Ludwig Institute for Cancer Research, Stockholm Branch, SE-171 77 Stockholm, Sweden.
authors.forename: Banafsheh
authors.initials: B
authors.lastname: Kadkhodaei
authors.forename: Takehito
authors.initials: T
authors.lastname: Ito
authors.forename: Eliza
authors.initials: E
authors.lastname: Joodmardi
authors.forename: Bengt
authors.initials: B
authors.lastname: Mattsson
authors.forename: Claude
authors.initials: C
authors.lastname: Rouillard
authors.forename: Manolo
authors.initials: M
authors.lastname: Carta
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Muramatsu
authors.forename: Chiho
authors.initials: C
authors.lastname: Sumi-Ichinose
authors.forename: Takahide
authors.initials: T
authors.lastname: Nomura
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Eva
authors.initials: E
authors.lastname: Lindqvist
authors.forename: Nils-Göran
authors.initials: NG
authors.lastname: Larsson
authors.forename: Lars
authors.initials: L
authors.lastname: Olson
authors.forename: Anders
authors.initials: A
authors.lastname: Björklund
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ichinose
authors.forename: Thomas
authors.initials: T
authors.lastname: Perlmann
mesh_terms: D000367:Age Factors; D000818:Animals; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D018390:Gene Targeting; D019426:Integrases / Q000235:genetics; D008636:Mesencephalon / Q000166:cytology* / Q000254:growth & development* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000166:cytology* / Q000502:physiology*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011247:Pregnancy
chemical_list: D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; C045073:Cre recombinase; D019426:Integrases