Nurr1-RXR heterodimers mediate RXR ligand-induced signaling in neuronal cells.
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.
Wallen-Mackenzie
Asa
A
The Ludwig Institute for Cancer Research, Stockholm Branch, S-171 77 Stockholm, Sweden.
Mata de Urquiza
Alexander
A
Petersson
Susanna
S
Rodriguez
Francisco J
FJ
Friling
Stina
S
Wagner
Joseph
J
Ordentlich
Peter
P
Lengqvist
Johan
J
Heyman
Richard A
RA
Arenas
Ernest
E
Perlmann
Thomas
T
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001921:Brain / Q000196:embryology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002822:Choriocarcinoma / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D005260:Female; D005656:Fungal Proteins; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D009930:Organic Chemicals; D051381:Rats; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D047488:Retinoid X Receptors; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology
D000924:Anticholesteremic Agents; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D015259:Dopamine Agents; D005656:Fungal Proteins; C423914:LG 268; D008024:Ligands; C539883:Nr4a2 protein, mouse; C539884:Nr4a2 protein, rat; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D009930:Organic Chemicals; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014212:Tretinoin