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

Sun Gyun Kim, Suho Lee, Yangsik Kim, Jieun Park, Doyeon Woo, Dayeon Kim, Yan Li, Wangyong Shin, Hyunjeong Kang, Chaehyun Yook, Minji Lee, Kyungdeok Kim, Junyeop Daniel Roh, Jeseung Ryu, Hwajin Jung, Seung Min Um, Esther Yang, Hyun Kim, Jinju Han, Won Do HeoEunjoon Kim

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Article number2695
JournalNature communications
Volume12
Issue number1
DOIs
Publication statusPublished - 2021 Dec

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Fingerprint

Dive into the research topics of 'Tanc2-mediated mTOR inhibition balances mTORC1/2 signaling in the developing mouse brain and human neurons'. Together they form a unique fingerprint.

Cite this