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

Abstract mTOR signaling, involving mTORC1 and mTORC2 complexes, critically regulates neural development and is implicated in various brain disorders. mTORC1/2 components that stimulate mTOR kinase activity strongly affect neurodevelopment, but mTOR-inhibitory mTORC1/2 components do not, questioning the role of balanced mTOR regulation in neurodevelopment. We found 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 directly interacts with and inhibits mTOR, which is suppressed by mTOR-activating serum or ketamine, a fast-acting antidepressant. Tanc2 and Deptor, known to inhibit mTORC1/2 but minimally affect neurodevelopment, distinctly inhibit mTOR in early- and late-stage neurons. Patient-derived Tanc2 mutations disable Tanc2 function, and human Tanc2 inhibits mTORC1/2. Therefore, Tanc2 represents a novel mTORC1/2 inhibitor with strong neurodevelopmental impacts, implicating mTOR inhibition in treating TANC2-related brain disorders and Tanc2 modulation in treating mTOR-related disorders.