Retinoic acid-gated sequence-specific translational control by RARα

• Published in: Proceedings of the National Academy of Sciences - PNAS 2008-12, Vol.105 (51), p.20303-20308
• Main Authors: Poon, Michael M, Chen, Lu
• Format: Article
• Language: English
• Subjects: Biological Sciences; Brain; Dendrites; Five prime untranslated regions; Gene expression regulation; Messenger RNA; Neurons; Proteins; Receptors; RNA; RNA binding proteins
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0807740105

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 RARα and is independent of transcriptional regulation. The molecular basis of this translational regulation by RA/RARα signaling, however, is unknown. Here we show that RARα is actively exported from the nucleus. Cytoplasmic RARα 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 RARα carboxyl terminal F-domain and specific sequence motifs in the 5'UTR of the GluR1 mRNA. Moreover, RARα association with the GluR1 mRNA directly underlies the translational control of GluR1 by RA: RARα represses GluR1 translation, while RA binding to RARα 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/RARα signaling.