Dopamine Neuron Agenesis in Nurr1-Deficient Mice

Abstract

Dopamine neurons of the substantia nigra and ventral tegmental area regulate movement and affective behavior and degenerate in Parkinson's disease. The orphan nuclear receptor Nurr1 was shown to be expressed in developing dopamine neurons before the appearance of known phenotypic markers for these cells. Mice lacking Nurr1 failed to generate midbrain dopaminergic neurons, were hypoactive, and died soon after birth. Nurr1 expression continued into adulthood, and brains of heterozygous animals, otherwise apparently healthy, contained reduced dopamine levels. These results suggest that putative Nurr1 ligands may be useful for treatment of Parkinson's disease and other disorders of midbrain dopamine circuitry.

Adult mice with reduced Nurr1 expression: an animal model for schizophrenia

“…Nurr1 heterozygous ( þ /À) mice were generated as previously described. 16 The line was backcrossed for over nine generations with C57Bl/6J mice. The genotype of each animal was determined by polymerase chain reaction of tail DNA using specific probes for the Nurr1 gene.…”

“…Nurr1 ( þ /À) mice have decreased DA levels at 2 months after birth but at 5 months striatal DA is normalized. 16 Nurr1 ( þ /À) male mice were found to have reduced mesolimbic and mesocortical DA levels accompanied with increases in locomotor activity. 24 Since the Nurr1 gene is expressed not only during the development of mesencephalic DA neurons but also is important for differentiating neurons, subtle dysregulations in this transcription factor may result in chronic alterations in DA transmission associated with symptoms of schizophrenia.…”

“…Nurr1 has been identified as a critical genetic factor for the terminal differentiation of midbrain DA neurons in the SNpc and VTA. [16][17][18] Nurr1 has also been shown to regulate key genes of critical importance for DA neurotransmission. 16,19,20 Nurr1 is expressed predominantly in limbic areas and in the ventral midbrain DA neurons, where its distribution overlaps with DA-containing neurons.…”

“…[16][17][18] Nurr1 has also been shown to regulate key genes of critical importance for DA neurotransmission. 16,19,20 Nurr1 is expressed predominantly in limbic areas and in the ventral midbrain DA neurons, where its distribution overlaps with DA-containing neurons. 21 Since Nurr1 expression continues into adulthood, its role in controlling DA neurons has important implications not only for the developing brain, but also for the adult brain.…”

“…16 The Nurr1 heterozygous ( þ /À) mice were investigated in a range of behavioral tests relevant for the DA and glutamate hypothesis of schizophrenia.…”