The non-essential TSC complex component TBC1D7 restricts tissue mTORC1 signaling and brain and neuron growth
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Date
2022-05-17
Publication Type
Journal Article
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yes
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Abstract
The tuberous sclerosis complex (TSC) 1 and 2 proteins associate with TBC1D7 to form the TSC complex, which is an essential suppressor of mTOR complex 1 (mTORC1), a ubiquitous driver of cell and tissue growth. Loss-of-function mutations in TSC1 or TSC2, but not TBC1D7, give rise to TSC, a pleiotropic disorder with aberrant activation of mTORC1 in various tissues. Here, we characterize mice with genetic deletion of Tbc1d7, which are viable with normal growth and development. Consistent with partial loss of function of the TSC complex, Tbc1d7 knockout (KO) mice display variable increases in tissue mTORC1 signaling with increased muscle fiber size but with strength and motor defects. Their most pronounced phenotype is brain overgrowth due to thickening of the cerebral cortex, with enhanced neuron-intrinsic mTORC1 signaling and growth. Thus, TBC1D7 is required for full TSC complex function in tissues, and the brain is particularly sensitive to its growth-suppressing activities.
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published
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Journal / series
Volume
39 (7)
Pages / Article No.
110824
Publisher
Elsevier
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Subject
mTOR; rapamycin; tuberous sclerosis complex; mouse model; Tsc1; hamartin; Tsc2; tuberin; TBC1D7; megalencephaly; brain; neurons; gait; growth
Organisational unit
09690 - Mitchell, James (ehemalig) / Mitchell, James (former)