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.
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.
Castillo
S O
SO
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1766, USA.
Baffi
J S
JS
Palkovits
M
M
Goldstein
D S
DS
Kopin
I J
IJ
Witta
J
J
Magnuson
M A
MA
Nikodem
V M
VM
D000818:Animals; D015415:Biomarkers; D001923:Brain Chemistry / Q000235:genetics; D004268:DNA-Binding Proteins; D004298:Dopamine / Q000096:biosynthesis* / Q000172:deficiency / Q000502:physiology; D005091:Exons; D005260:Female; D006579:Heterozygote; D007031:Hypothalamus / Q000378:metabolism*; D007980:Levodopa / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D016254:Mutagenesis, Insertional; D009474:Neurons / Q000378:metabolism*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D010641:Phenotype; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*; D017557:Ventral Tegmental Area / Q000378:metabolism* / Q000473:pathology
D015415:Biomarkers; D004268:DNA-Binding Proteins; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D012333:RNA, Messenger; D014157:Transcription Factors; D007980:Levodopa; D004298:Dopamine