Requirements for heterodimerization between the orphan nuclear receptor Nurr1 and retinoid X receptors

The nuclear receptor nurr1 is a transcription factor involved in the development and maintenance of neurons synthesizing the neurotransmitter dopamine. Although the lack of nurr1 expression has dramatic consequences for these cells either in terms of differentiation or survival, the mechanisms by which nurr1 controls gene transcription still remain unclear. In the intent to understand better the modalities of action of this nuclear receptor, we have undertaken a systematic analysis of the transcriptional effects and DNA binding properties of nurr1 as a monomer or when forming dimers with the different isotypes of the retinoic X receptor (RXR). Here, we show that nurr1 acts as a gene activator independently of RXR and through an AF2-independent mechanism. In addition, heterodimerization with RXR is isotype-specific, involves multiple domains in the C-terminal region of nurr1, and requires RXR binding to DNA. RXRalpha-nurr1 and RXRgamma-nurr1 heterodimers bind direct repeat response elements and display no specific requirements with respect to half-site spacing. However, the retinoid responsiveness of DNA-bound heterodimers requires the reiteration of at least three nurr1 binding sites, thereby limiting retinoid-induced nurr1 transcriptional activity to specific direct response elements.