Normalizing translation through 4E-BP prevents mTOR-driven cortical mislamination and ameliorates aberrant neuron integration
Normalizing translation through 4E-BP prevents mTOR-driven cortical mislamination and ameliorates aberrant neuron integration
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DOI：
10.1073/pnas.1605740113
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发表时间：
2016-10-04
影响因子：
11.1
通讯作者：
Bordey, Angelique
中科院分区：
文献类型：
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作者：
Lin, Tiffany V.;Hsieh, Lawrence;Bordey, Angelique
多动哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）是以异常脑细胞结构为特征的几种神经发育障碍的共同分子标志。负责这些缺陷的mTORC 1下游机制仍不清楚。我们发现，局部增加mTORC 1活性在皮质发育后期导致异位放置上层皮质神经元，不需要改变放射状胶质细胞的信号，并伴随着层特异性分子身份的变化。重要的是，我们发现，减少帽依赖性翻译表达的组成型活性突变体的翻译阻遏真核起始因子4 E结合蛋白1（4 E-BP 1）防止神经元错位和索马扩大，同时部分挽救树突肥大诱导的过度活跃mTORC 1。此外，通过敲低4 E-BP 2单独过度激活翻译足以诱导神经元错位。这些数据表明，异常脑细胞结构的许多方面可以通过操纵mTORC 1下游的单个细胞内过程，帽依赖性翻译来预防。
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.