The non-essential TSC complex component TBC1D7 restricts tissue mTORC1 signaling and brain and neuron growth

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.

Automated summary

TBC1D7 is an essential component of the TSC complex, which suppresses the growth of cells and tissues driven by mTORC1. In this study, Tbc1d7 knockout mice exhibited increased muscle fiber size, strength and motor defects, and overgrowth of the brain. These findings indicate that TBC1D7 is crucial for the full functionality of the TSC complex in tissues, with the brain being particularly sensitive to its growth-suppressing activities.