The Steroid/thyroid Hormone Receptor Superfamily

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Nurr1 is a transcription factor, a member of the superfamily of nuclear hormone receptors. To investigate the physiological role of Nurr1, we previously generated mice with a null mutation in the Nurr1 gene. Subsequent analysis revealed the absence of neurotransmitter dopamine, dopamine biosynthesizing enzymes, transporters and receptors for dopamine utilization in the central dopaminergic area of newborn pups. We have also shown that the neuroepithelial cells undergo normal ventralization and migration. These dopaminergic neuron precursors express general neuronal markers such as a neuronal nuclear marker and project to the striatum. The TUNEL assay showed no difference in the number of apoptotic cells between Nurr1-null and wild type mice. Hence, our results show that the transcription factor Nurr1 is required for terminal maturation of mesencephalic dopaminergic neurons, while genesis of dopaminergic precursors, their survival, and selection of specific target innervation are not affected at the time of birth in mice lacking Nurr1 gene function. In order to investigate the role of Nurr1, a procedure for primary neuronal cultures was established. Recently, using primary midbrain neuronal cultures from newborn Nurr1 knockouts, we have shown that a population of neurons could be induced to express tyrosine hydroxylase, a key enzyme in dopamine biosynthesis, in the presence of forskolin with a synergistic increase in the number of tyrosine hydroxylase expression neurons when combined with brain-derived neurotrophic factor and dopamine. These data indicate that midbrain neurons from Nurr1 knockout pups retain the capacity for the induced expression of tyrosine hydroxylase even though in vivo tyrosine hydroylase expression is absent. Thus, the factors, such as forskolin, brain-derived neurotrophic factor, and dopamine induce tyrosine hydroxylase expression via a pathway independent of Nurr1. Recently, we have used DNA microarray technology and probes derived from the midbrain of the ventral tegmental area of wild type and Nurr1 knockout mice. We have identified 40 genes whose expression is affected by Nurr1. It appears that Nurr1 can function as a repressor and inducer of the expression of specific genes. Using independent methods (Northern analyses and in situ hybridization), we are comfirming changes in the expression of Nurr1 target genes. We have tested the wild type and Nurr1-null heterozygous mice for locomotor activity. Locomotor activity was recorded in a photocell monitor after exposure to novelty and saline injection. Nurr1 heterozygous mice displayed significantly greater motor activity in the novel open field and after saline injection. These data demonstrate that the loss of a single allele of Nurr1 gene results in alteration in motor activity in response to mild stress.