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
Affiliations
Sandra Schrötter
Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA
Christopher J. Yuskaitis
Kirby Neurobiology Center, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
Michael R. MacArthur
Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA
Sarah J. Mitchell
Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA
Aaron M. Hosios
Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA
Maria Osipovich
Kirby Neurobiology Center, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
Margaret E. Torrence
Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA
James R. Mitchell
Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA
Gerta Hoxhaj
Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA
Mustafa Sahin
Kirby Neurobiology Center, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
Brendan D. Manning
Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA; Corresponding author
Summary: 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.
