Normalizing translation through 4E-BP prevents mTOR-driven cortical mislamination and ameliorates aberrant neuron integration

Proc Natl Acad Sci U S A. 2016 Oct 4;113(40):11330-11335. doi: 10.1073/pnas.1605740113. Epub 2016 Sep 19.

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.

Keywords: autism; cortical development; dendrite; mTOR; spine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Carrier Proteins / metabolism*
  • Cell Cycle Proteins
  • Dendritic Spines / metabolism
  • Eukaryotic Initiation Factors / metabolism*
  • Excitatory Postsynaptic Potentials
  • Gene Knockdown Techniques
  • Green Fluorescent Proteins / metabolism
  • Matrix Attachment Region Binding Proteins / metabolism
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Neuroglia / metabolism
  • Neurons / metabolism*
  • Phosphoproteins / metabolism*
  • Protein Biosynthesis*
  • RNA Caps / metabolism
  • RNA, Small Interfering / metabolism
  • Ras Homolog Enriched in Brain Protein / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism*
  • Transcription Factors / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Cell Cycle Proteins
  • Eif4ebp1 protein, mouse
  • Eif4ebp2 protein, mouse
  • Eukaryotic Initiation Factors
  • Matrix Attachment Region Binding Proteins
  • Phosphoproteins
  • RNA Caps
  • RNA, Small Interfering
  • Ras Homolog Enriched in Brain Protein
  • Rheb protein, mouse
  • SATB2 protein, mouse
  • Transcription Factors
  • Green Fluorescent Proteins
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1