Lack of zinc finger protein 521 upregulates dopamine β-hydroxylase expression in the mouse brain, leading to abnormal behavior
Lack of zinc finger protein 521 upregulates dopamine β-hydroxylase expression in the mouse brain, leading to abnormal behavior
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DOI：
10.1016/j.lfs.2019.116559
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发表时间：
2019-08-15
期刊：
影响因子：
6.1
通讯作者：
Mitsuda, Noriaki
中科院分区：
文献类型：
--
作者：
Ohkubo, Nobutaka;Aoto, Mamoru;Mitsuda, Noriaki
目的：以前，我们报道了大多数Zfp521编码区缺陷的小鼠(Zfp521(Delta/Delta)小鼠)表现出异常的行为，包括多动和低焦虑。在本研究中，我们旨在阐明单胺变化的参与及其机制。主要方法：首先，我们用酶联免疫吸附试验比较了Zfp521(Delta/Delta)和Zfp521(+/+)小鼠脑内多巴胺(DA)、去甲肾上腺素(NA)和5-羟色胺(5-羟色胺)的水平。接下来，我们利用定量聚合酶链式反应和Western blotting阐明了其作用机制。主要结果：Zfp521(Delta/Delta)小鼠脑内DA水平降低，NA水平升高。我们发现ZFP521抑制多巴胺β-羟基酶(DBH)的表达，该酶将DA转化为NA。我们还证明了与胸径相关的转录因子--同源结构域转录因子2和早期生长反应蛋白-1参与了ZFP521对胸径的上调。给予DBH的特异性抑制剂奈匹卡司可减轻Zfp521(Delta/Delta)小鼠的异常行为。意义：这些结果表明，ZFP 521的缺失上调了DBH的表达，从而导致脑中DA水平的下降和NA水平的升高，从而导致行为异常。
Aim: Previously, we reported that mice deficient in most of the Zfp521 coding region (Zfp521(Delta/Delta) mice) displayed abnormal behaviors, including hyperlocomotion and lower anxiety. In this study, we aimed to elucidate the involvement and mechanisms of monoamine variation.Main methods: First, we compared the levels of dopamine (DA), noradrenaline (NA), and serotonin in the brains of Zfp521(Delta/Delta) and Zfp521(+/+) mice using enzyme-linked immunosorbent assay. Next, we elucidated the mechanisms using quantitative PCR and Western Blotting. Additionally, we administered inhibitory drug to the mice and performed behavioral tests.Key findings: Our results showed that the DA level decreased and the NA level increased in Zfp521(Delta/Delta)mice. We found that ZFP521 suppresses the expression of dopamine beta-hydroxylase (DBH), which converts DA into NA. We also demonstrated that paired homeodomain transcription factor 2 and early growth response protein-1, which are the transcription factors for Dbh, were involved in the upregulation of Dbh by ZFP521. The administration of nepicastat, a specific inhibitor of DBH, attenuated the abnormal behaviors of Zfp521(Delta/Delta) mice.Significance: These results suggest that the lack of ZFP521 upregulates the expression of DBH, which leads to a decrease in the DA level and an increase in the NA level in the brain, resulting in abnormal behaviors.