Retinoic acid-gated sequence-specific translational control by RARα

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