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

Area of Science:

• Cellular Biology
• Genetics
• Neuroscience

Background:

• The tuberous sclerosis complex (TSC) 1 and 2 proteins form a complex that suppresses mTOR complex 1 (mTORC1).
• Loss-of-function mutations in TSC1 or TSC2 cause TSC, a disorder characterized by uncontrolled mTORC1 activation.
• TBC1D7's role in TSC complex function and its impact on mTORC1 signaling were not fully understood.

Purpose of the Study:

• To investigate the in vivo function of TBC1D7 by creating and analyzing Tbc1d7 knockout (KO) mice.
• To determine the necessity of TBC1D7 for the full suppressor activity of the TSC complex.
• To assess the impact of TBC1D7 deficiency on mTORC1 signaling and tissue growth, particularly in the brain.

Main Methods:

• Genetic deletion of Tbc1d7 in mice to create KO models.
• Assessment of mouse viability, growth, and development.
• Analysis of mTORC1 signaling pathways in various tissues.
• Evaluation of muscle fiber size, strength, and motor function.
• Histological examination of brain structures, focusing on cerebral cortex thickness and neuronal growth.

Main Results:

• Tbc1d7 KO mice were viable with normal overall growth but exhibited partial loss of TSC complex function.
• Increased mTORC1 signaling and muscle fiber size were observed, alongside strength and motor deficits.
• A pronounced phenotype of brain overgrowth, specifically cerebral cortex thickening, was identified in KO mice.
• Neuron-intrinsic mTORC1 signaling and growth were enhanced in the absence of TBC1D7.

Conclusions:

• TBC1D7 is essential for the complete suppressor function of the TSC complex in mammalian tissues.
• The brain is particularly sensitive to the growth-suppressing effects of TBC1D7.
• TBC1D7 deficiency leads to aberrant mTORC1 activation and tissue overgrowth, contributing to neurological phenotypes.