TY - JOUR
T1 - Tanc2-mediated mTOR inhibition balances mTORC1/2 signaling in the developing mouse brain and human neurons
AU - Kim, Sun Gyun
AU - Lee, Suho
AU - Kim, Yangsik
AU - Park, Jieun
AU - Woo, Doyeon
AU - Kim, Dayeon
AU - Li, Yan
AU - Shin, Wangyong
AU - Kang, Hyunjeong
AU - Yook, Chaehyun
AU - Lee, Minji
AU - Kim, Kyungdeok
AU - Roh, Junyeop Daniel
AU - Ryu, Jeseung
AU - Jung, Hwajin
AU - Um, Seung Min
AU - Yang, Esther
AU - Kim, Hyun
AU - Han, Jinju
AU - Heo, Won Do
AU - Kim, Eunjoon
N1 - Funding Information:
We would like to Dr Kwang-Wook Choi in the Department of Biological Sciences at KAIST for thoughtful comments on the manuscript. This work was supported by the Ministry of Health & Welfare (HI18C1077 to J.H.), NRF Grant 2017M3C7A1079692 (to H.K.), and the Institute for Basic Science (IBS-R002-A1 to J.H. and IBS-R002-D1 to E.K.).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85105770875&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-22908-4
DO - 10.1038/s41467-021-22908-4
M3 - Article
C2 - 33976205
AN - SCOPUS:85105770875
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2695
ER -