Nucleus Millennium in Stress and Addiction, Santiago, Chile.
J Neurochem. 2010 Aug;114(4):1158-67. doi: 10.1111/j.1471-4159.2010.06841.x. Epub 2010 Jun 1.
Genesis of midbrain dopamine (DA) neurons depends on Nurr1, a nuclear receptor expressed during development and adulthood in these neurons. Nurr1 is required for the expression of genes of dopaminergic phenotype such as tyrosine hydroxylase and DA transporter. The expression of the tyrosine kinase receptor RET also depends on Nurr1 during development. However, it is unknown whether RET expression is regulated by Nurr1 during adulthood, and the mechanism by which Nurr1 regulates RET expression. Using an adeno-associated vector-delivered anti-Nurr1 ribozyme, we knocked-down Nurr1 expression unilaterally in the substantia nigra (SN) of adult rats. Animals injected with the ribozyme displayed a 57.3% decrease in Nurr1 mRNA in the SN accompanied by decreased DA extracellular levels in the striatum. RET mRNA in the injected SN and RET protein in the ipsilateral striatum decreased 76.9% and 47%, respectively. Tyrosine hydroxylase and DA transporter mRNA did not change in Nurr1 knocked-down SN. Nurr1 induced the transcription of the human RET promoter in cell type and concentration-dependent manner. Nurr1 induction of RET promoter is independent of NBRE elements. These results show that the expression of RET in rat adult SN is regulated by Nurr1 and suggest that RET is a transcriptional target of this nuclear receptor.
中脑多巴胺 (DA) 神经元的起源取决于 Nurr1，这是一种在这些神经元的发育和成年期表达的核受体。Nurr1 是多巴胺能表型基因如酪氨酸羟化酶和 DA 转运体表达所必需的。酪氨酸激酶受体 RET 的表达也依赖于发育过程中的 Nurr1。然而，尚不清楚 RET 表达是否在成年期受到 Nurr1 的调节，以及 Nurr1 调节 RET 表达的机制。使用腺相关载体递送的抗 Nurr1 核酶，我们在成年大鼠的黑质 (SN) 单侧敲低了 Nurr1 的表达。用核酶注射的动物在 SN 中的 Nurr1 mRNA 减少了 57.3%，伴随着纹状体中 DA 细胞外水平的降低。注射 SN 中的 RET mRNA 和同侧纹状体中的 RET 蛋白分别减少了 76.9%和 47%。Nurr1 敲低的 SN 中的酪氨酸羟化酶和 DA 转运体 mRNA 没有变化。Nurr1 以细胞类型和浓度依赖的方式诱导人 RET 启动子的转录。Nurr1 诱导 RET 启动子的转录不依赖于 NBRE 元件。这些结果表明，RET 在大鼠成年 SN 中的表达受 Nurr1 调节，并表明 RET 是该核受体的转录靶标。
