Nurr1 regulates Top IIβ and functions in axon genesis of mesencephalic dopaminergic neurons

Background: NURR1 (also named as NR4A2) is a member of the steroid/thyroid hormone receptor family, which can bind to DNA and modulate expression of target genes. Previous studies have shown that NURR1 is essential for the nigral dopaminergic neuron phenotype and function maintenance, and the defects of the gene are possibly associated with Parkinson's disease (PD). Results: In this study, we used new born Nurr1 knock-out mice combined with Affymetrix genechip technology and real time polymerase chain reaction (PCR) to identify Nurr1 regulated genes, which led to the discovery of several transcripts differentially expressed in the nigro-striatal pathway of Nurr1 knock-out mice. We found that an axon genesis gene called Topoisomerase II (Top II) was down-regulated in Nurr1 knock-out mice and we identified two functional NURR1 binding sites in the proximal Top II promoter. While in Top II null mice, we saw a significant loss of dopaminergic neurons in the substantial nigra and lack of neurites along the nigro-striatal pathway. Using specific TOP II antagonist ICRF-193 or Top II siRNA in the primary cultures of ventral mesencephalic (VM) neurons, we documented that suppression of TOP II expression resulted in VM neurites shortening and growth cones collapsing. Furthermore, microinjection of ICRF-193 into the mouse medial forebrain bundle (MFB) led to the loss of nigro-striatal projection. Conclusion: Taken together, our findings suggest that Top II might be a down-stream target of Nurr1, which might influence the processes of axon genesis in dopaminergic neurons via the regulation of TOP II expression. The Nurr1-Top II interaction may shed light on the pathologic role of Nurr1 defect in the nigro-striatal pathway deficiency associated with PD.