The nuclear transcription factor RARalpha associates with neuronal RNA granules and suppresses translation.
All-trans-retinoic acid stimulates dendritic growth in hippocampal neurons within minutes by activating mitogen-activated protein kinase and mTOR and increasing dendritic translation of calcium calmodulin-dependent protein kinase II alpha and the alpha-amino-3-hydroxyl-5-methyl-4-isoxazole propionate receptor subunit GluR1. Hippocampal neurons express RARalpha in dendrites, and knocking down RARalpha prevents all-trans-retinoic acid effects on dendritic growth. Here we show, by liquid chromatography/mass spectrometry analysis of immunoaffinity isolates of hippocampal neurons, that RARalpha partners with many RNA-binding proteins and translation factors conveyed in dendritic RNA transport granules, including the purine-rich element-binding protein, Pur alpha. The interaction of RARalpha with Pur alpha, an RNA-binding protein required for dendritic RNA transport, and other RNA-binding proteins was confirmed by tandem affinity purification. Confocal microscopy confirmed localization of neuronal RARalpha in dendritic RNA granules with Pur alpha and FMRP (the fragile x mental retardation protein). Hippocampal RARalpha also associates with mRNA, e.g. encoding GluR1 and calcium calmodulin-dependent protein kinase II alpha. Consistent with a granule function of conveying translationally silenced mRNA, RARalpha inhibits translation initiation, independent of 7-methylguanylate cap or poly(A) tail, and prompts mRNA redistribution to silencing ribonucleoprotein particles. These data afford a mechanism for rapid stimulation of dendritic growth by all-trans-retinoic acid and reveal that the ligand-dependent transcription factor RARalpha also regulates translation.
Chen
Na
N
Department of Nutritional Science and Toxicology, University of California, Berkeley, CA 94720, USA.
Onisko
Bruce
B
Napoli
Joseph L
JL
D000199:Actins / Q000378:metabolism; D000818:Animals; D002522:Chlorocebus aethiops; D002853:Chromatography, Liquid / Q000379:methods; D004268:DNA-Binding Proteins / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D014176:Protein Biosynthesis; D012313:RNA / Q000737:chemistry*; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D013569:Synapses / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D000199:Actins; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; C076035:c-MYC-associated zinc finger protein; D012313:RNA