The Steroid/thyroid Hormone Receptor Superfamily

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1. 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. We have identified some genes whose expression is affected by Nurr1. It appears that Nurr1 can function either as a repressor or inducer of the expression of specific genes. Using comparative microarray analysis of RNAs from wild type and Nurr1-null mice prepared from the ventral tegmental area has shown a large decrease in guanosine triphosphate cyclohydrolase (GTPCH) mRNA in Nurr1-null pups, which led to concomitant reduction in BH4 content. Microarray analysis showed 70% reduction in GTPCH expression in the ventral tegmental area of both 12.5-day old Nurr1-null embryos and neonates. Although levels of GTPCH mRNA increased significantly between E12.5 and birth in wild type mice, no such change was seen in the null neonates. The promoter deletional analyses revealed that Nurr1 activates GTPCH transcription in the absence of NGF1-B response element. 2. We have also decided to investigate whether Nurr1 is involved in differentiation of other cell types. Understanding mechanisms involved in regulation of body weight is a very important goal due to the worldwide obesity epidemic. Recently, we discovered that Nurr1-null heterozygous mice have twice as much fat mass when compared to wild type mice when fed with either normal or high fat diet without significant differences in food intake. By hormonal induction, mouse embryonic fibroblasts (MEF) generated from Nurr1-null mice have shown increased rate of adipocyte differentiation as estimated by accumulation of oil droplets in contrast to MEF prepared from wild type littermates. When Nurr1 was constitutively overexpressed, using retroviral infection in MEF-Nurr1-null, the rate of adipogenesis was comparable to that observed in MEF wild type. In agreement with these results, the level of molecular markers of adipogenesis C/EBP alpha and PPAR gamma was increased in the absence and decreased in the presence of Nurr1, respectively. These results suggest that Nurr1 functions as a repressor of adipogenesis in vivo and in vitro and might play a role in adipogenesis differentiation linked to obesity. Our recent results indicate that the level of Nurr1 mRNA in early stages of adipogenesis is increased. Thus, that in turn, Nurr1 can regulate expression of known repressors of adipogensis. It has been reported that the preadipocyte factor 1, (Pref-1), is highly expressed in preadipocytes and is nearly absent in differentiated adipocytes. We have found that during adipogenesis, in the presence of Nurr1 overexpression, the level of Pref-1 is substantially elevated, possibly leading to inhibition of adipocyte differentiation.