The Non-essential TSC Complex Component TBC1D7 Restricts Tissue MTORC1 Signaling and Brain and Neuron Growth

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2022 May 18

PMID 35584673

Authors

Sandra Schrotter

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

Soon will be listed here.

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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References

Switon K, Kotulska K, Janusz-Kaminska A, Zmorzynska J, Jaworski J . Molecular neurobiology of mTOR. Neuroscience. 2016; 341:112-153. DOI: 10.1016/j.neuroscience.2016.11.017. View

Magri L, Cambiaghi M, Cominelli M, Alfaro-Cervello C, Cursi M, Pala M . Sustained activation of mTOR pathway in embryonic neural stem cells leads to development of tuberous sclerosis complex-associated lesions. Cell Stem Cell. 2011; 9(5):447-62. DOI: 10.1016/j.stem.2011.09.008. View

Kim J, Guan K . mTOR as a central hub of nutrient signalling and cell growth. Nat Cell Biol. 2019; 21(1):63-71. DOI: 10.1038/s41556-018-0205-1. View

Mendes C, Bartos I, Marka Z, Akay T, Marka S, Mann R . Quantification of gait parameters in freely walking rodents. BMC Biol. 2015; 13:50. PMC: 4511453. DOI: 10.1186/s12915-015-0154-0. View

Chen Y, Huang W, Sejourne J, Clipperton-Allen A, Page D . Pten Mutations Alter Brain Growth Trajectory and Allocation of Cell Types through Elevated β-Catenin Signaling. J Neurosci. 2015; 35(28):10252-67. PMC: 6605343. DOI: 10.1523/JNEUROSCI.5272-14.2015. View

Kobayashi T, Minowa O, Sugitani Y, Takai S, Mitani H, Kobayashi E . A germ-line Tsc1 mutation causes tumor development and embryonic lethality that are similar, but not identical to, those caused by Tsc2 mutation in mice. Proc Natl Acad Sci U S A. 2001; 98(15):8762-7. PMC: 37509. DOI: 10.1073/pnas.151033798. View

Onda H, Lueck A, Marks P, WARREN H, Kwiatkowski D . Tsc2(+/-) mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background. J Clin Invest. 1999; 104(6):687-95. PMC: 408440. DOI: 10.1172/JCI7319. View

Capo-Chichi J, Tcherkezian J, Hamdan F, Decarie J, Dobrzeniecka S, Patry L . Disruption of TBC1D7, a subunit of the TSC1-TSC2 protein complex, in intellectual disability and megalencephaly. J Med Genet. 2013; 50(11):740-4. DOI: 10.1136/jmedgenet-2013-101680. View

Amende I, Kale A, McCue S, Glazier S, Morgan J, Hampton T . Gait dynamics in mouse models of Parkinson's disease and Huntington's disease. J Neuroeng Rehabil. 2005; 2:20. PMC: 1201165. DOI: 10.1186/1743-0003-2-20. View

10.

Yang H, Yu Z, Chen X, Li J, Li N, Cheng J . Structural insights into TSC complex assembly and GAP activity on Rheb. Nat Commun. 2021; 12(1):339. PMC: 7804450. DOI: 10.1038/s41467-020-20522-4. View

11.

Carson R, Van Nielen D, Winzenburger P, Ess K . Neuronal and glia abnormalities in Tsc1-deficient forebrain and partial rescue by rapamycin. Neurobiol Dis. 2011; 45(1):369-80. PMC: 3225598. DOI: 10.1016/j.nbd.2011.08.024. View

12.

Collins S, Wagner C, Gagliardi L, Kretz P, Fischer M, Kessler P . A Method for Parasagittal Sectioning for Neuroanatomical Quantification of Brain Structures in the Adult Mouse. Curr Protoc Mouse Biol. 2018; 8(3):e48. DOI: 10.1002/cpmo.48. View

13.

Dhamne S, Silverman J, Super C, Lammers S, Hameed M, Modi M . Replicable in vivo physiological and behavioral phenotypes of the null mutant mouse model of autism. Mol Autism. 2017; 8:26. PMC: 5472997. DOI: 10.1186/s13229-017-0142-z. View

14.

Alfaiz A, Micale L, Mandriani B, Augello B, Pellico M, Chrast J . TBC1D7 mutations are associated with intellectual disability, macrocrania, patellar dislocation, and celiac disease. Hum Mutat. 2014; 35(4):447-51. DOI: 10.1002/humu.22529. View

15.

Kassai H, Sugaya Y, Noda S, Nakao K, Maeda T, Kano M . Selective activation of mTORC1 signaling recapitulates microcephaly, tuberous sclerosis, and neurodegenerative diseases. Cell Rep. 2014; 7(5):1626-1639. DOI: 10.1016/j.celrep.2014.04.048. View

16.

Zeng L, Xu L, Gutmann D, Wong M . Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol. 2008; 63(4):444-53. PMC: 3937593. DOI: 10.1002/ana.21331. View

17.

Kobayashi T, Minowa O, KUNO J, Mitani H, Hino O, Noda T . Renal carcinogenesis, hepatic hemangiomatosis, and embryonic lethality caused by a germ-line Tsc2 mutation in mice. Cancer Res. 1999; 59(6):1206-11. View

18.

Choi Y, Di Nardo A, Kramvis I, Meikle L, Kwiatkowski D, Sahin M . Tuberous sclerosis complex proteins control axon formation. Genes Dev. 2008; 22(18):2485-95. PMC: 2546692. DOI: 10.1101/gad.1685008. View

19.

Griffith J, Wong M . The mTOR pathway in treatment of epilepsy: a clinical update. Future Neurol. 2018; 13(2):49-58. PMC: 6261508. DOI: 10.2217/fnl-2018-0001. View

20.

Bar-Peled L, Chantranupong L, Cherniack A, Chen W, Ottina K, Grabiner B . A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science. 2013; 340(6136):1100-6. PMC: 3728654. DOI: 10.1126/science.1232044. View