The Steroid/thyroid Hormone Receptor Superfamily

类固醇/甲状腺激素受体超家族

• 批准号: 7593639
• 负责人: Vera M Nikodem
• 金额: $ 55.42万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7593639
• 关键词: Anabolism; Birth; Clinical; Cultured Cells; Development; Disease; Disruption; Dopamine; Elements; Embryo; Gene Targeting; Genes; Genetic Transcription; Guanosine Triphosphate; Knockout Mice; Messenger RNA; Microarray Analysis; Midbrain structure; Mus; Neurons; Nuclear; Orphan; Parkinson Disease; Pathology; Property; Proteins; Regulation; Reporting; Schizophrenia; Site; Small Interfering RNA; Steroids; Thyroid Hormone Receptor; Tyrosine; Ventral Tegmental Area; Wild Type Mouse; cofactor; comparative; day; dopamine transporter; dopaminergic neuron; homologous recombination; neonate; prevent; promoter; pup; tetrahydrobiopterin; transcription factor

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.

在小鼠中，通过同源重组破坏Nurr1基因，阻止发育中的多巴胺神经元前体，阻止多巴胺神经元特异性蛋白的表达，导致神经递质多巴胺合成的完全抑制。通过对野生型和Nurr1缺失小鼠的RNA进行比较微阵列分析，从腹侧被盖区制备的RNA显示，Nurr1缺失幼鼠的鸟苷三磷酸环水解酶mRNA大幅下降，导致四氢生物蝶呤的伴随减少，四氢生物蝶呤是多巴胺生物合成中酪氨酸水解酶的重要辅助因子。基因芯片分析显示，在12.5天大的Nurr1缺失胚胎和新生儿的腹侧被盖区，鸟苷三磷酸环水解酶的表达降低了70%。虽然野生型小鼠的鸟苷三磷酸环水解酶mRNA水平在胚胎12.5至出生期间显著增加，但在未出生的小鼠中未见这种变化。此外，针对Nurr1的小干扰RNA降低了细胞培养中鸟苷三磷酸环水解酶的表达。启动子缺失分析表明，Nurr1在没有Nurr1反应元件样位点的情况下激活鸟苷三磷酸环水解酶转录，类似于最近报道的Nurr1对多巴胺转运体的调控。

项目成果

Differential role of ERK in cAMP-induced Nurr1 expression in N2A and C6 cells.

ERK 在 N2A 和 C6 细胞中 cAMP 诱导的 Nurr1 表达中的不同作用。

• DOI: 10.1097/00001756-200401190-00020
• 发表时间: 2004
• 期刊: Neuroreport
• 影响因子: 1.7
• 作者: Lee,MiKyeong;Nikodem,VeraM
• 通讯作者: Nikodem,VeraM

Nigrostriatal innervation is preserved in Nurr1-null mice, although dopaminergic neuron precursors are arrested from terminal differentiation.

• DOI: 10.1016/s0169-328x(00)00211-4
• 发表时间: 2000-12
• 期刊: Brain research. Molecular brain research
• 作者: J. Witta;J. Baffi;M. Palkovits;Éva Mezey;S. O. Castillo;V. M. Nikodem