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Normalizing translation through 4E-BP prevents mTOR-driven cortical mislamination and ameliorates aberrant neuron
Tiffany V Lin1, Lawrence Hsieh1, Tomoki Kimura1
1Department 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.
Summary
Hyperactive mammalian target of rapamycin complex 1 (mTORC1) signaling causes neurodevelopmental defects. Targeting cap-dependent translation downstream of mTORC1 can prevent abnormal brain cytoarchitecture in these disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Developmental Biology
Background:
- Hyperactive mammalian target of rapamycin complex 1 (mTORC1) is implicated in neurodevelopmental disorders with abnormal brain cytoarchitecture.
- Downstream mechanisms of mTORC1 leading to these defects are not fully understood.
Purpose of the Study:
- To investigate the downstream molecular mechanisms of mTORC1 responsible for abnormal brain cytoarchitecture.
- To determine if targeting cap-dependent translation can prevent these defects.
Main Methods:
- Focal increase of mTORC1 activity during late corticogenesis in mouse models.
- Manipulation of cap-dependent translation using eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and 4E-BP2.
- Analysis of neuronal placement, soma size, and dendritic morphology.
Main Results:
- Increased mTORC1 activity caused ectopic placement of upper-layer cortical neurons and altered molecular identity.
- Decreasing cap-dependent translation via active 4E-BP1 prevented neuronal misplacement and partially rescued dendritic hypertrophy.
- Overactivating translation by knocking down 4E-BP2 induced neuronal misplacement.
Conclusions:
- Cap-dependent translation is a critical downstream effector of mTORC1 in regulating neuronal migration and morphology.
- Modulating cap-dependent translation offers a potential therapeutic strategy for neurodevelopmental disorders characterized by abnormal brain cytoarchitecture.
