Tanc2-mediated mTOR inhibition balances mTORC1/2 signaling in the developing mouse brain and human neurons

• Published in: Nature communications Vol. 12; no. 1; p. 2695
• Main Authors: Kim, Sun-Gyun, Lee, Suho, Kim, Yangsik, Park, Jieun, Woo, Doyeon, Kim, Dayeon, Li, Yan, Shin, Wangyong, Kang, Hyunjeong, Yook, Chaehyun, Lee, Minji, Kim, Kyungdeok, Roh, Junyeop Daniel, Ryu, Jeseung, Jung, Hwajin, Um, Seung Min, Yang, Esther, Kim, Hyun, Han, Jinju, Heo, Won Do, Kim, Eunjoon
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.05.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 14; 14/32; 14/34; 631/378/2571/1696; 631/378/340; 631/378/87; 631/80/86; 64; 64/60; 9/30; 96; Adaptor proteins; Animals; Antidepressants; Brain; Brain - embryology; Brain - growth & development; Brain - metabolism; Cells (biology); Cells, Cultured; Embryos; Enzyme inhibitors; HEK293 Cells; Humanities and Social Sciences; Humans; Hyperactivity; Immunosuppressive Agents - pharmacology; Ketamine; Kinases; Learning Disabilities - genetics; Learning Disabilities - physiopathology; Lethality; Maze Learning - drug effects; Maze Learning - physiology; Mechanistic Target of Rapamycin Complex 1 - metabolism; Mechanistic Target of Rapamycin Complex 2 - metabolism; Memory Disorders - genetics; Memory Disorders - physiopathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbalances; multidisciplinary; Neural stem cells; Neurodevelopment; Neuronal Plasticity - drug effects; Neuronal Plasticity - genetics; Neuronal Plasticity - physiology; Neurons; Neurons - metabolism; Progenitor cells; Proteins; Proteins - genetics; Proteins - metabolism; Rapamycin; Scaffolding; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - drug effects; Signaling; Sirolimus - pharmacology; TOR protein; TOR Serine-Threonine Kinases - metabolism
• ISSN: 2041-1723; 2041-1723
• 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. Alterations of the mTOR signalling pathway are associated with neurodevelopmental defects. Regulators of the mTOR kinase activity are not fully described. Here, the authors show that Tanc2, a scaffolding protein, acts as a direct inhibitor of mTOR kinase activity in the developing mouse brain and cultured human neurons.