Lack of zinc finger protein 521 upregulates dopamine β-hydroxylase expression in the mouse brain, leading to abnormal behavior.

Previously, we reported that mice deficient in most of the Zfp521 coding region (Zfp521Δ/Δ mice) displayed abnormal behaviors, including hyperlocomotion and lower anxiety. In this study, we aimed to elucidate the involvement and mechanisms of monoamine variation. First, we compared the levels of dopamine (DA), noradrenaline (NA), and serotonin in the brains of Zfp521Δ/Δ 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. Our results showed that the DA level decreased and the NA level increased in Zfp521Δ/Δ mice. We found that ZFP521 suppresses the expression of dopamine β-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 Zfp521Δ/Δ mice. 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.