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The non-essential TSC complex component TBC1D7 restricts tissue mTORC1 signaling and brain and neuron growth.
Schrötter, Sandra; Yuskaitis, Christopher J; MacArthur, Michael R; Mitchell, Sarah J; Hosios, Aaron M; Osipovich, Maria; Torrence, Margaret E; Mitchell, James R; Hoxhaj, Gerta; Sahin, Mustafa; Manning, Brendan D.
Affiliation
  • Schrötter S; 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.
  • Yuskaitis CJ; Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • MacArthur MR; Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • Mitchell SJ; Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • Hosios AM; 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.
  • Osipovich M; Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Torrence ME; Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • Mitchell JR; Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • Hoxhaj G; Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • Sahin M; Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Manning BD; 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. Electronic address: bmanning@hsph.harvard.edu.
Cell Rep ; 39(7): 110824, 2022 05 17.
Article in En | MEDLINE | ID: mdl-35584673
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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Tuberous Sclerosis / Brain / Tumor Suppressor Proteins / Intracellular Signaling Peptides and Proteins / Mechanistic Target of Rapamycin Complex 1 / Tuberous Sclerosis Complex 1 Protein / Neurons Type of study: Prognostic_studies Limits: Animals Language: En Journal: Cell Rep Year: 2022 Document type: Article Affiliation country:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Tuberous Sclerosis / Brain / Tumor Suppressor Proteins / Intracellular Signaling Peptides and Proteins / Mechanistic Target of Rapamycin Complex 1 / Tuberous Sclerosis Complex 1 Protein / Neurons Type of study: Prognostic_studies Limits: Animals Language: En Journal: Cell Rep Year: 2022 Document type: Article Affiliation country: