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Nat Commun ; 12(1): 2695, 2021 05 11.
Article in English | MEDLINE | ID: mdl-33976205

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.


Subject(s)
Brain/metabolism , Mechanistic Target of Rapamycin Complex 1/metabolism , Mechanistic Target of Rapamycin Complex 2/metabolism , Neurons/metabolism , Proteins/metabolism , TOR Serine-Threonine Kinases/metabolism , Animals , Brain/embryology , Brain/growth & development , Cells, Cultured , HEK293 Cells , Humans , Immunosuppressive Agents/pharmacology , Learning Disabilities/genetics , Learning Disabilities/physiopathology , Maze Learning/drug effects , Maze Learning/physiology , Memory Disorders/genetics , Memory Disorders/physiopathology , Mice, Inbred C57BL , Mice, Knockout , Neuronal Plasticity/drug effects , Neuronal Plasticity/genetics , Neuronal Plasticity/physiology , Proteins/genetics , Signal Transduction/drug effects , Sirolimus/pharmacology
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