Nurr1-RXR heterodimers mediate RXR ligand-induced signaling in neuronal cells

Wallen-Mackenzie A, De Urquiza AM, Petersson S, Rodriguez FJ, Friling S, Wagner J, Ordentlich P, Lengqvist J, Heyman RA, Arenas E and Perlmann T
Source: Genes Dev
Publication Date: (2003)
Issue: 17(24): 3036-3047
Research Area:
Cells used in publication:
Neuron, hippo/cortical, rat
Species: rat
Tissue Origin: brain
Rat primary cortical neurons were co-transfected with vectors encoding Gal4-Nurr1 or a heterodimerization-defective protein Gal4-Nurrdim, together with a Gal4-responsive luciferase reporter vector. Incubation with a synthetic RXR-specific agonist activates Gal4-Nurr but not Gal4-Nurrdim. An RXR-specific antagonist blocks this response. Thus, Gal4-Nurr can form heterodimers with endogenous RXR, which have a potential to transduce signaling by RXR ligands. In a further experiment, a specific RXR-Nurr heterodimer activating compound selectively activated neurons co-transfected with Gal4-responsive luciferase reporter vector together with Gal4-Nurr, but not together with Gal4-Nurrdim. This suggests Nurr to be an essential heterodimer partner in RXR-ligand induced neuronal survival.
The retinoid X receptor (RXR) is essential as a common heterodimerization partner of several nuclear receptors (NRs). However, its function as a bona fide receptor for endogenous ligands has remained poorly understood. Such a role would depend on the existence of RXR activating ligands in vivo and on the ability of such ligands to influence relevant biological functions. Here we demonstrate the presence of endogenous RXR ligands in the embryonic central nervous system (CNS) and show that they can activate heterodimers formed between RXR and the orphan NR Nurr1 in vivo. Moreover, RXR ligands increase the number of surviving dopaminergic cells and other neurons in a process mediated by Nurr1-RXR heterodimers. These results provide evidence for a role of Nurr1 as a ligand-independent partner of RXR in its function as a bona fide ligand-activated NR. Finally, our findings identify RXR-Nurr1 heterodimers as a potential target in the treatment of neurodegenerative disease.