Tbc1d7-KO Mouse

Tbc1d7, Tre2-Bub2-Cdc16-1 domain family member 7, is a component of the tuberous sclerosis complex (TSC) [1,2,3,4,5,6,7,8]. The TSC complex, composed of TSC1, TSC2, and Tbc1d7, is an essential suppressor of mTOR complex 1 (mTORC1), a key promoter of cell growth. This complex is involved in the PI3K-mTORC1 signaling network, which directs cellular metabolism and growth [1,4,7]. Dysregulation of this network has been linked to diverse pathologies [1].

Genetic deletion of Tbc1d7 in mice shows variable increases in tissue mTORC1 signaling, with increased muscle fiber size but strength and motor defects. The most pronounced phenotype is brain overgrowth due to thickening of the cerebral cortex, with enhanced neuron-intrinsic mTORC1 signaling and growth, indicating Tbc1d7 is required for full TSC complex function in tissues, and the brain is particularly sensitive to its growth-suppressing activities [2]. In humans, Tbc1d7 mutations are associated with intellectual disability, macrocrania, patellar dislocation, and celiac disease. Patient cell lines show increased phosphorylation of 4EBP1 (a downstream target of mTORC1) and a delay in autophagy initiation [3].

In conclusion, Tbc1d7 is crucial for the function of the TSC complex in restricting mTORC1 signaling and cell growth. Mouse models with Tbc1d7 knockout have revealed its role in tissue development, especially in the brain. In humans, Tbc1d7 mutations are associated with specific disease conditions related to abnormal mTORC1 activation, highlighting the importance of Tbc1d7 in maintaining normal physiological functions [2,3].

References:

1. Dibble, Christian C, Cantley, Lewis C. 2015. Regulation of mTORC1 by PI3K signaling. In Trends in cell biology, 25, 545-55. doi:10.1016/j.tcb.2015.06.002. https://pubmed.ncbi.nlm.nih.gov/26159692/

2. Schrötter, Sandra, Yuskaitis, Christopher J, MacArthur, Michael R, Sahin, Mustafa, Manning, Brendan D. . The non-essential TSC complex component TBC1D7 restricts tissue mTORC1 signaling and brain and neuron growth. In Cell reports, 39, 110824. doi:10.1016/j.celrep.2022.110824. https://pubmed.ncbi.nlm.nih.gov/35584673/

3. Alfaiz, Ali Abdullah, Micale, Lucia, Mandriani, Barbara, Merla, Giuseppe, Reymond, Alexandre. . TBC1D7 mutations are associated with intellectual disability, macrocrania, patellar dislocation, and celiac disease. In Human mutation, 35, 447-51. doi:10.1002/humu.22529. https://pubmed.ncbi.nlm.nih.gov/24515783/

4. Dibble, Christian C, Elis, Winfried, Menon, Suchithra, Murphy, Leon O, Manning, Brendan D. 2012. TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. In Molecular cell, 47, 535-46. doi:10.1016/j.molcel.2012.06.009. https://pubmed.ncbi.nlm.nih.gov/22795129/

5. Santiago Lima, Arthur Jorge, Hoogeveen-Westerveld, Marianne, Nakashima, Akio, Kikkawa, Ushio, Nellist, Mark. 2014. Identification of regions critical for the integrity of the TSC1-TSC2-TBC1D7 complex. In PloS one, 9, e93940. doi:10.1371/journal.pone.0093940. https://pubmed.ncbi.nlm.nih.gov/24714658/

6. Capo-Chichi, José-Mario, Tcherkezian, Joseph, Hamdan, Fadi F, Roux, Philippe P, Michaud, Jacques L. 2013. Disruption of TBC1D7, a subunit of the TSC1-TSC2 protein complex, in intellectual disability and megalencephaly. In Journal of medical genetics, 50, 740-4. doi:10.1136/jmedgenet-2013-101680. https://pubmed.ncbi.nlm.nih.gov/23687350/

7. Hartung, Josephine, Müller, Christine, Calkhoven, Cornelis F. 2024. The dual role of the TSC complex in cancer. In Trends in molecular medicine, , . doi:10.1016/j.molmed.2024.10.009. https://pubmed.ncbi.nlm.nih.gov/39488444/

8. Gai, Zhongchao, Chu, Wendan, Deng, Wei, Nellist, Mark, Wu, Geng. . Structure of the TBC1D7-TSC1 complex reveals that TBC1D7 stabilizes dimerization of the TSC1 C-terminal coiled coil region. In Journal of molecular cell biology, 8, 411-425. doi:10.1093/jmcb/mjw001. https://pubmed.ncbi.nlm.nih.gov/26798146/