title: DDX3 Modulates Neurite Development via Translationally Activating an RNA Regulon Involved in Rac1 Activation.
abstract: The RNA helicase DDX3 is a component of neuronal granules, and its gene mutations are linked to intellectual disability (ID). Here we demonstrate that DDX3 depletion in neurons impairs neurite development by downregulating Rac1 level and activation. Moreover, DDX3 activates the translation of functionally coherent mRNAs involved in Rac1 activation including Rac1 Among the DDX3 regulon, Prkaca encodes the catalytic subunit of PKA, a potential activator of Rac1 in neurons. DDX3-modulated PKAcα and Rac1 expression tunes the strength of PKA-Rac1 signaling and thereby contributes to neurite outgrowth and dendritic spine formation. Inhibition of DDX3 activity or expression in neonatal mice impaired dendritic outgrowth and spine formation of hippocampal neurons, echoing neuronal deficits underling DDX3 mutation-associated ID. Finally, we provide evidence that DDX3 activates local protein synthesis through a 5' UTR-dependent mechanism in neurons. The novel DDX3 regulon may conduct a spatial and temporal control of Rac1 signaling to regulate neurite development.
  
  
  
  DDX3X mutations are linked to intellectual disability (ID). We provide first evidence that DDX3 is required for neurite outgrowth and dendritic spine formation in vitro and in vivo We identified a DDX3 regulon constituting functionally cohesive mRNAs involved in Rac1 signaling, which contributes to DDX3-modulated neurite development. Inhibition or ablation of DDX3 in vivo shortened neurite lengths and impaired dendritic spine formation in hippocampal neurons, reflecting the prevalence of ID-associated DDX3X mutations in the helicase domain. Mechanistically, DDX3 activates local protein synthesis of mRNAs sharing similar 5' UTR structures and therefore controls Rac1 signaling strength in neurites.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Hung-Hsi
authors.initials: HH
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Hsin-I
authors.initials: HI
authors.lastname: Yu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan wtarn@ibms.sinica.edu.tw.
authors.forename: Woan-Yuh
authors.identifier: 0000-0001-6244-6639
authors.initials: WY
authors.lastname: Tarn
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D005576:Colforsin / Q000494:pharmacology; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000378:metabolism; D053487:DEAD-box RNA Helicases; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D016501:Neurites / Q000502:physiology* / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020365:RNA Helicases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D051176:beta Catenin / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D014665:Vasodilator Agents; D051176:beta Catenin; D005576:Colforsin; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C463959:protein kinase A Calpha; D053487:DEAD-box RNA Helicases; C514697:Ddx3x protein, mouse; D020365:RNA Helicases; D020830:rac1 GTP-Binding Protein; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
keywords: PKA signaling; RNA helicase; dendritic spines; neurite outgrowth; translational control