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. 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 mRNA in Nurr1-null pups, which led to concomitant reduction in tetrahydrobiopterin, an essential cofactor for tyrosine hydroylase in dopamine biosynthesis. Microarray analysis showed 70% reduction in guanosine triphosphate cyclohydrolase expression in the ventral tegmental area of both 12.5-day old Nurr1-null embryos and neonates. Although levels of guanosine triphosphate cyclohydrolase mRNA increased significantly between E12.5 and birth in wild type mice, no such change was seen in the null neonates. In addition, small interfering RNA targeted against Nurr1 decreased guanosine triphosphate cyclohydrolase expresssion in cell culture. The promoter deletional analyses revealed that Nurr1 activates guanosine triphosphate cyclohydrolase transcription in the absence of Nurr1 responsive element-like sites, similarly, as recently reported for dopamine transporter regulation by Nurr1.
