title: Normalizing translation through 4E-BP prevents mTOR-driven cortical mislamination and ameliorates aberrant neuron integration.
abstract: Hyperactive mammalian target of rapamycin complex 1 (mTORC1) is a shared molecular hallmark in several neurodevelopmental disorders characterized by abnormal brain cytoarchitecture. The mechanisms downstream of mTORC1 that are responsible for these defects remain unclear. We show that focally increasing mTORC1 activity during late corticogenesis leads to ectopic placement of upper-layer cortical neurons that does not require altered signaling in radial glia and is accompanied by changes in layer-specific molecular identity. Importantly, we found that decreasing cap-dependent translation by expressing a constitutively active mutant of the translational repressor eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) prevents neuronal misplacement and soma enlargement, while partially rescuing dendritic hypertrophy induced by hyperactive mTORC1. Furthermore, overactivation of translation alone through knockdown of 4E-BP2 was sufficient to induce neuronal misplacement. These data show that many aspects of abnormal brain cytoarchitecture can be prevented by manipulating a single intracellular process downstream of mTORC1, cap-dependent translation.
authors.affiliation: Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Tiffany V
authors.initials: TV
authors.lastname: Lin
authors.affiliation: Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Hsieh
authors.affiliation: Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Taylor J
authors.initials: TJ
authors.lastname: Malone
authors.affiliation: Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520 angelique.bordey@yale.edu.
authors.forename: Angélique
authors.initials: A
authors.lastname: Bordey
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D049229:Dendritic Spines / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000378:metabolism; D036961:Matrix Attachment Region Binding Proteins / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism; D051379:Mice; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D014176:Protein Biosynthesis; D012315:RNA Caps / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D000076205:Ras Homolog Enriched in Brain Protein / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; C491255:Eif4ebp2 protein, mouse; D039642:Eukaryotic Initiation Factors; D036961:Matrix Attachment Region Binding Proteins; D010750:Phosphoproteins; D012315:RNA Caps; D034741:RNA, Small Interfering; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; C501473:SATB2 protein, mouse; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: autism; cortical development; dendrite; mTOR; spine