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

Xin Heng,Xuping Li,Weidong Le,Gang Jin,Dehuang Yang,Shijun Fu,Mingzhe Zhu,Xin Zhang

doi:10.1186/1750-1326-7-4

Abstract

BackgroundNURR1 (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).ResultsIn 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.ConclusionTaken 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.

Highlights

NURR1 is a member of the steroid/thyroid hormone receptor family, which can bind to DNA and modulate expression of target genes
Agenesis of dopaminergic neuron axons in Nurr1 knockout mice and in Nurr1 deficient SH-SY5Y cell line Sagittal sections of postnatal brains of wide type (WT), Nurr1+/- and Nurr1-/- mice were stained with tyrosine hydroxylase (TH) antibody
Based on our previous work at our lab using zebra fish model, we found that the dopaminergic neurons still exists in the posterior tuberculum of the zebra fish after we knocked down NURR1 expression level using morpholino technique, suggesting that NURR1 may play an important role in the differentiation and maturation rather than the survival of dopaminergic progenitors in the posterior tuberculum area during zebrafish embryogenesis [29]

Summary

Introduction

NURR1 ( 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). One of the most important functions MDNs possess is the control over voluntary movements Their degeneration in substantial nigra (SN) is a hallmark of Parkinson’s disease (PD) [2]. NURR1, a transcription factor belonging to the orphan nuclear receptor superfamily, recognizes DNA by binding hormone-response elements in the promoters of Recently, increasing evidence reveals that NURR1 may influence the development and differentiation of MDNs through the regulation of axon genesis. PTPRs have been involved in axonal growth and guidance [22] These data raise the possibility that NURR1 may play an important role either directly or indirectly in the fasciculation of dopaminergic axons

Objectives

Methods

Results

Discussion

Conclusion