Dopamine biosynthesis is selectively abolished in substantia nigra/ventral tegmental area but not in hypothalamic neurons in mice with targeted disruption of the Nurr1 gene

Susan O. Castillo, Judit S. Baffi, M. Palkóvits, David S. Goldstein, Irwin J. Kopin, Jassir Witta, Mark A. Magnuson, Vera M. Nikodem

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Abstract

To ascertain the function of an orphan nuclear receptor Nurr1, a transcription factor belonging to a large gene family that includes receptors for steroids, retinoids, and thyroid hormone, we generated Nurr1-null mice by homologous recombination. Mice, heterozygous for a single mutated Nurr1 allele, appear normal, whereas mice homozygous for the null allele die within 24 h after birth. Dopamine (DA) was absent in the substantia nigra (SN) and ventral tegmental area (VTA) of Nurr1-null mice, consistent with absent tyrosine hydroxylase (TH), L-aromatic amino acid decarboxylase, and other DA neuron markers. TH immunoreactivity and mRNA expression in hypothalamic, olfactory, and lower brain stem regions were unaffected. L- Dihydroxyphenylalanine treatments, whether given to the pregnant dams or to the newborns, failed to rescue the Nurr1-null mice. We were unable to discern differences between null and wild-type mice in the cellularity, presence of neurons, or axonal projections to the SN and VTA. These findings provide evidence for a new mechanism of DA depletion in vivo and suggest a unique role for Nurr1 in fetal development and/or postnatal survival.

Original languageEnglish
Pages (from-to)36-46
Number of pages11
JournalMolecular and Cellular Neuroscience
Volume11
Issue number1-2
DOIs
Publication statusPublished - May 1998

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Ventral Tegmental Area
Substantia Nigra
Dopamine
Neurons
Genes
Tyrosine 3-Monooxygenase
Nuclear Receptor Subfamily 4, Group A, Member 2
Alleles
Aromatic-L-Amino-Acid Decarboxylases
Dihydroxyphenylalanine
Steroid Receptors
Dopaminergic Neurons
Homologous Recombination
Retinoids
Fetal Development
Thyroid Hormones
Brain Stem
Transcription Factors
Parturition
Messenger RNA

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Developmental Neuroscience

Cite this

Dopamine biosynthesis is selectively abolished in substantia nigra/ventral tegmental area but not in hypothalamic neurons in mice with targeted disruption of the Nurr1 gene. / Castillo, Susan O.; Baffi, Judit S.; Palkóvits, M.; Goldstein, David S.; Kopin, Irwin J.; Witta, Jassir; Magnuson, Mark A.; Nikodem, Vera M.

In: Molecular and Cellular Neuroscience, Vol. 11, No. 1-2, 05.1998, p. 36-46.

Research output: Contribution to journalArticle

Castillo, Susan O. ; Baffi, Judit S. ; Palkóvits, M. ; Goldstein, David S. ; Kopin, Irwin J. ; Witta, Jassir ; Magnuson, Mark A. ; Nikodem, Vera M. / Dopamine biosynthesis is selectively abolished in substantia nigra/ventral tegmental area but not in hypothalamic neurons in mice with targeted disruption of the Nurr1 gene. In: Molecular and Cellular Neuroscience. 1998 ; Vol. 11, No. 1-2. pp. 36-46.
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