@article{700c2560fa654c08b3f3313e6f25bc28,
title = "The non-essential TSC complex component TBC1D7 restricts tissue mTORC1 signaling and brain and neuron growth",
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.",
keywords = "brain, CP: Developmental biology, CP: Neuroscience, gait, growth, hamartin, megalencephaly, mouse model, mTOR, neurons, rapamycin, TBC1D7, Tsc1, Tsc2, tuberin, tuberous sclerosis complex",
author = "Sandra Schr{\"o}tter and Yuskaitis, {Christopher J.} and MacArthur, {Michael R.} and Mitchell, {Sarah J.} and Hosios, {Aaron M.} and Maria Osipovich and Torrence, {Margaret E.} and Mitchell, {James R.} and Gerta Hoxhaj and Mustafa Sahin and Manning, {Brendan D.}",
note = "Funding Information: B.D.M. is a member of the scientific advisory board and a shareholder of Navitor Pharmaceuticals. M.S. reports grant support from Novartis, Biogen, Astellas, Aeovian, Bridgebio, and Aucta and is on the scientific advisory boards for Novartis, Roche, Regenxbio, SpringWorks Therapeutics, Jaguar Therapeutics, and Alkermes. All other authors declare no competing financial interests. Funding Information: We thank Meghan Wilkinson, Lina Du, and colleagues at the Harvard Medical School Transgenic Mouse Core, the Animal Behavior and Physiology Core at Boston Children's Hospital Intellectual and Developmental Disabilities Research Center (NIH P50HD105351), and the Dana-Farber/Harvard Cancer Center (P30CA06516) Rodent Histopathology Core for technical assistance. This work was supported by grants from the German Research Foundation/DFG (SCHR 1611/1-1, Project 403153940) to S.S. the TSC Alliance to G.H. and the NIH (R35-CA197459 and P01-CA120964) to B.D.M. Conceptualization, S.S. and B.D.M.; investigation, S.S. M.R.M. S.J.M. C.J.Y. M.O. A.M.H. M.E.T. and G.H; writing, S.S. and B.D.M.; funding acquisition, S.S. G.H. and B.D.M.; resources, B.D.M. J.R.M. and M.S.; supervision, B.D.M. J.R.M. and M.S. B.D.M. is a member of the scientific advisory board and a shareholder of Navitor Pharmaceuticals. M.S. reports grant support from Novartis, Biogen, Astellas, Aeovian, Bridgebio, and Aucta and is on the scientific advisory boards for Novartis, Roche, Regenxbio, SpringWorks Therapeutics, Jaguar Therapeutics, and Alkermes. All other authors declare no competing financial interests. Funding Information: We thank Meghan Wilkinson, Lina Du, and colleagues at the Harvard Medical School Transgenic Mouse Core, the Animal Behavior and Physiology Core at Boston Children{\textquoteright}s Hospital Intellectual and Developmental Disabilities Research Center ( NIH P50HD105351 ), and the Dana-Farber/Harvard Cancer Center ( P30CA06516 ) Rodent Histopathology Core for technical assistance. This work was supported by grants from the German Research Foundation /DFG (SCHR 1611/1-1, Project 403153940 ) to S.S., the TSC Alliance to G.H., and the NIH ( R35-CA197459 and P01-CA120964 ) to B.D.M. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = may,
day = "17",
doi = "10.1016/j.celrep.2022.110824",
language = "English (US)",
volume = "39",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "7",
}