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. 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 confirmed changes in the expression of Nurr1 target genes. Guanosine triphosphate cyclohydrolase (GTPCH) is the rate-limiting enzyme in the synthesis of tetra-hydrobiopterin (BH4) which is a very important component of thyrosine hydroxyase (TH) activity. BH4 is synthesized from GTP sequentially by GTPCH and two other enzymes. In most situations, BH4 is at a subsaturating level so that any changes in BH4 availability, either by alteration in GTPCH activity or expression level, affect BH4 and consequently TH activity. Using comparative microarray analysis of RNAs from wild type and Nurr1-null mice prepared from the ventral tagmental area has shown a large decrease in GTPCH mRNA in Nurr1 null pups, which led to concomitant reduction in BH4 content. Thus, GTPCH would be the first enzyme in dopamine biosynthesis that appear to regulate neurotransmission in the prefrontal cortex and nucleus accumbens. Furthermore, mutations in the Nurr1 gene have been recently identified in schizophrenic patients. Although Nurr1 is essential for differentiation of mesencephalic neurons, its role in mature dopamine neurons has not been determined. No significant difference in the density of wild and heterozygous TH-immunoreactive neurons was found between these two genotypically different groups. This indicates that in vivo, dopamine neurons are not affected by the Nurr1 genotype. In order to investigate the role of Nurr1 in survival of dopamine neurons in vitro postnatal mesocortical neurons were cultured from Nurr1 heterozygous and wild type littermates. Postnatal cultures revealed a significant reduction only in the survival of TH immunoreactive neurons derived from Nurr1 heterozygous pups as early as 1 day in culture. Furthermore, the total length of neurites was less than that seen in the controls. The differential degree of survival and reduced neurite growth of the Nurr1 heterozygous TH immunoreactive neurons in vitro and the observation that in vivo there is no substantial differnce in the intensity and density of TH immunoreactive neurons in the Nurr1 wild and heterozygous genotypes, demonstrate that under "environmental insult" (dispersion and growth in culture) and genetic susceptibility (loss of one Nurr1 allele) the Nurr1 heterozygous neurons are at significant disadvantage. This scenario might be similar to that proposed for Parkinson's disorder when a combination of genetic factors and environmental toxins accelerate dopamine neuron death.