The Steroid/thyroid Hormone Receptor Superfamily

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The majority of central nervous system dopamine is located in the nigrostriatal, mesolimbic and mesocortical systems. The nigrostriatal system is comprised of neuron cell bodies located in the substantia nigra pars compacta and innervating the striatum. The mesolimbic and mesocortical system consists of neuron cell bodies in the ventral tegmental area and innervating the limbic areas, including the nucleus accumbens and the cortex, respectively. Alterations in dopamine neurotransmission have been implicated in a number of neurological conditions including Parkinson's disease, schizophrenia, attention deficit hyperactivity disorder, and drug addiction. The nuclear orphan receptor Nurr1 is essential for the terminal differentiation of midbrain neurons as we and others showed. The arrest of dopamine neuron precursors in development, by disruption of the Nurr1 gene by homologous recombination in mice, prevents expression of dopamine neuron specific proteins leading to the complete inhibition of neuron transmitter dopamine synthesis. In order to investigate the role of Nurr1, a procedure for primary neuronal cultures was extablished. 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 limited capacity for the induced expression of tyrosine hydroxylase even though in vivo tyrosing hydrylase expression is absent. Thus, the factors, such as foskolin, brain-derived neurotrophic factor, and dopamine induce tyrosine hydroxylase expression via a pathway independent of Nurr1. We have also 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 reponse to mild stress. 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 some 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 (real time polymerase chain reaction and in situ hybridization), we are confirming changes in the expression of Nurr1 target genes.