Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762, USA.
J Mol Neurosci. 2012 Mar;46(3):545-53. doi: 10.1007/s12031-011-9642-z. Epub 2011 Sep 20.
The NR4A transcription factors NR4A1, NR4A2, and NR4A3 (also known as Nur77, Nurr1, and Nor1, respectively) share similar DNA-binding properties and have been implicated in regulation of dopamine neurotransmission genes. Our current hypothesis is that NR4A gene expression is regulated by dopamine neuron activity and that induction of NR4A genes will increase expression of dopamine neurotransmission genes. Eticlopride and γ-butyrolactone (GBL) were used in wild-type (+/+) and Nurr1-null heterozygous (+/-) mice to determine the mechanism(s) regulating Nur77 and Nurr1 expression. Laser capture microdissection and real-time PCR was used to measure Nurr1 and Nur77 mRNA levels in the ventral tegmental area (VTA). Nur77 expression was significantly elevated 1 h after both GBL (twofold) and eticlopride (fourfold). In contrast, GBL significantly decreased Nurr1 expression in both genotypes, while eticlopride significantly increased Nurr1 expression only in the +/+ mice. In a separate group of mice, haloperidol injection significantly elevated Nur77 and Nor1, but not Nurr1 mRNA in the VTA within 1 h and significantly increased tyrosine hydroxylase (TH) and dopamine transporter (DAT) mRNA expression by 4 h. These data demonstrate that the NR4A genes are dynamically regulated in dopamine neurons with maintenance of Nurr1 expression requiring dopamine neuron activity while both attenuation of dopamine autoreceptors activation and dopamine neuronal activity combining to induce Nur77 expression. Additionally, these data suggest that induction of NR4A genes could regulate TH and DAT expression and ultimately regulate dopamine neurotransmission.
NR4A 转录因子 NR4A1、NR4A2 和 NR4A3（分别也称为 Nur77、Nurr1 和 Nor1）具有相似的 DNA 结合特性，并被认为参与调节多巴胺神经递质基因。我们目前的假设是，NR4A 基因表达受多巴胺神经元活性调节，并且 NR4A 基因的诱导将增加多巴胺神经递质基因的表达。依托必利和 γ-丁内酯 (GBL) 用于野生型 (+/+) 和 Nurr1 杂合缺失 (+/-) 小鼠，以确定调节 Nur77 和 Nurr1 表达的机制。激光捕获显微切割和实时 PCR 用于测量腹侧被盖区 (VTA) 中的 Nurr1 和 Nur77 mRNA 水平。GBL（两倍）和依托必利（四倍）给药 1 小时后，Nur77 表达显著升高。相比之下，GBL 显著降低了两种基因型中的 Nurr1 表达，而依托必利仅在 +/+ 小鼠中显著增加了 Nurr1 表达。在另一组小鼠中，氟哌啶醇注射在 1 小时内显著升高了 VTA 中的 Nur77 和 Nor1，但未升高 Nurr1 mRNA，并且在 4 小时内显著增加了酪氨酸羟化酶 (TH) 和多巴胺转运蛋白 (DAT) mRNA 的表达。这些数据表明，NR4A 基因在多巴胺神经元中动态调节，维持 Nurr1 表达需要多巴胺神经元活性，而同时减弱多巴胺自身受体激活和多巴胺神经元活性的组合诱导 Nur77 表达。此外，这些数据表明诱导 NR4A 基因可能调节 TH 和 DAT 表达，并最终调节多巴胺神经传递。
