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 SO, Baffi JS, Palkovits M, Goldstein DS, Kopin IJ, Witta J, Magnuson MA, Nikodem VM
Mol Cell Neurosci. 1998 11 (1-2): 36-46

PMID: 9608532 · DOI:10.1006/mcne.1998.0673

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.

MeSH Terms (22)

Animals Biomarkers Brain Chemistry DNA-Binding Proteins Dopamine Exons Female Heterozygote Hypothalamus Levodopa Mice Mice, Inbred C57BL Mice, Neurologic Mutants Mutagenesis, Insertional Neurons Nuclear Receptor Subfamily 4, Group A, Member 2 Phenotype Pregnancy RNA, Messenger Substantia Nigra Transcription Factors Ventral Tegmental Area

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