The Steroid/thyroid Hormone Receptor Superfamily

通过在小鼠中同源重组破坏Nurr 1基因，在发育中阻滞多巴胺神经元前体，阻止多巴胺神经元特异性蛋白的表达，导致神经元递质多巴胺合成的完全抑制。 使用比较微阵列分析的RNA从野生型和Nurr 1-null小鼠制备的腹侧被盖区显示了一个大的减少鸟苷三磷酸环化水解酶mRNA在Nurr 1-null幼崽，这导致了伴随减少四氢生物蝶呤，一个必要的辅因子酪氨酸水解酶在多巴胺的生物合成。 微阵列分析显示，在12.5天的Nurr 1基因缺失的胚胎和新生儿的腹侧被盖区，鸟苷三磷酸环化水解酶的表达减少了70%。 虽然鸟苷三磷酸环化水解酶的mRNA水平增加显着E12.5和出生之间的野生型小鼠，没有这样的变化被认为是在null新生儿。 此外，针对Nurr 1的小干扰RNA降低了细胞培养物中鸟苷三磷酸环化水解酶的表达。 启动子缺失分析表明，Nurr 1激活鸟苷三磷酸环水解酶转录的Nurr 1响应元件样网站的情况下，同样，最近报道的多巴胺转运蛋白调节Nurr 1。

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.