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

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 IIβ (Top IIβ) was down-regulated in Nurr1 knock-out mice and we identified two functional NURR1 binding sites in the proximal Top IIβ promoter. While in Top IIβ 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 IIβ siRNA in the primary cultures of ventral mesencephalic (VM) neurons, we documented that suppression of TOP IIβ 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.Taken together, our findings suggest that Top IIβ might be a down-stream target of Nurr1, which might influence the processes of axon genesis in dopaminergic neurons via the regulation of TOP IIβ expression. The Nurr1-Top IIβ interaction may shed light on the pathologic role of Nurr1 defect in the nigro-striatal pathway deficiency associated with PD.Mesencephalic dopaminergic neurons (MDNs) arise from a common set of precursors, but mature to direct a wide range of brain functions [1]. The common feature of these cells is their ability to regulate dopamine (DA) synthesis, transmission and uptake. One of the most important functions MDNs possess is the control over voluntary movements. Also, their degeneration in substantial nigra (SN) is a hallmark of Parkinson's disease (PD) [2]. It becomes a high priority to understand the molecular mechanism and pathway by which MDNs develop and maintain their functions [3,4]. NURR1, a transcription factor belongi