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

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

Author information

1
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.
2
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.

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

PMID:
27647922
PMCID:
PMC5056085
DOI:
10.1073/pnas.1605740113
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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