Retinoic acid-gated sequence-specific translational control by RARalpha.
Retinoic acid (RA) plays important roles in development by modulating gene transcription through nuclear receptor activation. Increasing evidence supports a role for RA and RA receptors (RARs) in synaptic plasticity in the brain. We have recently reported that RA mediates a type of homeostatic synaptic plasticity through activation of dendritic protein synthesis, a process that requires dendritically localized RARalpha and is independent of transcriptional regulation. The molecular basis of this translational regulation by RA/RARalpha signaling, however, is unknown. Here we show that RARalpha is actively exported from the nucleus. Cytoplasmic RARalpha acts as an RNA-binding protein that associates with a subset of mRNAs, including dendritically localized glutamate receptor 1 (GluR1) mRNA. This binding is mediated by the RARalpha carboxyl terminal F-domain and specific sequence motifs in the 5'UTR of the GluR1 mRNA. Moreover, RARalpha association with the GluR1 mRNA directly underlies the translational control of GluR1 by RA: RARalpha represses GluR1 translation, while RA binding to RARalpha reduces its association with the GluR1 mRNA and relieves translational repression. Taken together, our results demonstrate a ligand-gated translational regulation mechanism mediated by a non-genomic function of RA/RARalpha signaling.
Poon
Michael M
MM
Department of Molecular, University of California, Berkeley, CA 94720-3200, USA.
Chen
Lu
L
D000818:Animals; D001483:Base Sequence; D003712:Dendrites / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins; D051381:Rats; D018091:Receptors, AMPA / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin / Q000494:pharmacology*
D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D018091:Receptors, AMPA; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; C000607073:Rara protein, rat