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

Sandra Schrötter, Christopher J. Yuskaitis, Michael R. MacArthur, Sarah J. Mitchell, Aaron M. Hosios, Maria Osipovich, Margaret E. Torrence, James R. Mitchell, Gerta Hoxhaj, Mustafa Sahin, Brendan D. Manning

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Article number110824
JournalCell Reports
Volume39
Issue number7
DOIs
StatePublished - May 17 2022
Externally publishedYes

Keywords

  • CP: Developmental biology
  • CP: Neuroscience
  • TBC1D7
  • Tsc1
  • Tsc2
  • brain
  • gait
  • growth
  • hamartin
  • mTOR
  • megalencephaly
  • mouse model
  • neurons
  • rapamycin
  • tuberin
  • tuberous sclerosis complex

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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