The glucocorticoid receptor is a co-regulator of the orphan nuclear receptor Nurr1

Nurr1 (NR4A2) is an atypical nuclear receptor (NR) because of its inability to bind a ligand and to activate transcription following canonical NR rules. An affinity chromatography-based screen identified the glucocorticoid receptor (GR) as an interactant of Nurr1. The co-localization of these two NRs in the hippocampus and the substantia nigra, as well as their involvement in similar neurological processes led us to investigate the functional consequences of such a physical interaction. GR interfered with Nurr1 transcriptional activity, and Nurr1 association to GR confers glucocorticoid regulation to this orphan receptor. The N-terminal domain of Nurr1 interacts directly with GR, whereas several domains of GR can associate to Nurr1. The GR-mediated increase in Nurr1 transcriptional activity requires the N-terminal domain of GR, but not a functional DNA binding domain. Finally, SMRT and SRC2, two co-regulators of GR, modulated the transcriptional activity of the Nurr1-GR complex, but not that of Nurr1 alone. Our results therefore establish GR as a transcriptional regulator of Nurr1, and open new opportunities in the pharmacological regulation of Nurr1 by glucocorticoids in the CNS.