Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon, Korea.
Graduate School of Medical Science and Engineering, Korea Advanced Institute for Science and Technology (KAIST), Daejeon, Korea.
Nat Commun. 2021 May 11;12(1):2695. doi: 10.1038/s41467-021-22908-4.
mTOR signaling, involving mTORC1 and mTORC2 complexes, critically regulates neural development and is implicated in various brain disorders. However, we do not fully understand all of the upstream signaling components that can regulate mTOR signaling, especially in neurons. Here, we show a direct, regulated inhibition of mTOR by Tanc2, an adaptor/scaffolding protein with strong neurodevelopmental and psychiatric implications. While Tanc2-null mice show embryonic lethality, Tanc2-haploinsufficient mice survive but display mTORC1/2 hyperactivity accompanying synaptic and behavioral deficits reversed by mTOR-inhibiting rapamycin. Tanc2 interacts with and inhibits mTOR, which is suppressed by mTOR-activating serum or ketamine, a fast-acting antidepressant. Tanc2 and Deptor, also known to inhibit mTORC1/2 minimally affecting neurodevelopment, distinctly inhibit mTOR in early- and late-stage neurons. Lastly, Tanc2 inhibits mTORC1/2 in human neural progenitor cells and neurons. In summary, our findings show that Tanc2 is a mTORC1/2 inhibitor affecting neurodevelopment.
mTOR 信号通路，涉及 mTORC1 和 mTORC2 复合物，对神经发育具有关键调控作用，并与各种脑疾病有关。然而，我们并不完全了解所有能够调节 mTOR 信号通路的上游信号成分，特别是在神经元中。在这里，我们展示了 Tanc2 对 mTOR 的直接、受调控的抑制作用，Tanc2 是一种具有强烈神经发育和精神疾病意义的衔接蛋白/支架蛋白。虽然 Tanc2 基因敲除小鼠表现出胚胎致死性，但 Tanc2 杂合不足小鼠存活下来，但显示出 mTORC1/2 过度活跃，伴随突触和行为缺陷，可被 mTOR 抑制 rapamycin 逆转。Tanc2 与 mTOR 相互作用并抑制其活性，而 mTOR 激活物血清或快速抗抑郁药氯胺酮可抑制 Tanc2。Tanc2 和 Deptor 也被认为对 mTORC1/2 的抑制作用最小，对神经发育影响不大，但能在早期和晚期神经元中明显抑制 mTOR。最后，Tanc2 抑制人神经祖细胞和神经元中的 mTORC1/2。总之，我们的研究结果表明，Tanc2 是一种影响神经发育的 mTORC1/2 抑制剂。
