Tuberous sclerosis complex (TSC) is a multi-organ disease caused by mutations in either of the TSC1 or TSC2 genes, the products of which act as repressors of a fundamentally important kinase, mTORC1. Patients with TSC develop hamartomas (benign tumor-like overgrowths of normal mature cells) in the brain, kidney, skin, lung and heart. Brain hamartomas (known as ‘tubers’) are thought to cause the neurological manifestations of the disease, which include epilepsy, autism, mental retardation and psychiatric problems. Disease prognosis depends on the severity of the symptoms, which range from mild skin abnormalities to severe mental retardation, seizures and kidney failure. There is no cure, although mTORC1 inhibitors are currently being tested in clinical trials as a ‘rational’ therapeutic. Although mouse and rat models of TSC exist, many fundamental questions regarding the mechanisms of disease initiation and progression remain, particularly with respect to the development of brain tubers.
The authors develop a model system of TSC by introducing a premature stop codon in the zebrafish tsc2 gene (which encodes the protein tuberin). This tsc2vu242 allele prevents translation of the GTPase-activating protein (GAP) domain of tuberin, which is known to be required for TORC1 inhibition. Zebrafish homozygous for the tsc2vu242 mutation die at larval stages and have increased TORC1 signaling, abnormally large cells in the brain and liver, and forebrain disorganization. Heterozygous tsc2vu242 zebrafish have slight increases in TORC1 signaling but no abnormalities in cell size or tissue organization. Treatment of homozygous tsc2vu242 zebrafish with rapamycin, a potent and specific inhibitor of the TORC1 complex, reverses signaling abnormalities and restores cell size to normal. In transplantation experiments, tsc2-deficient cells have increased TORC1 signaling in a cell-autonomous manner, as expected. However, non-cell-autonomous effects are also observed, because mutant cells can recruit wild-type cells to ectopic regions of the host forebrain.
Implications and future directions
Although the precise roles of TSC1 and TSC2 genes during normal development, as well as during hamartoma formation in patients with TSC, remain elusive, it is clear that control of mTORC1 signaling is highly important for many aspects of the disease. This zebrafish model of TSC will enhance understanding of normal tuberin function, and of the cell-autonomous and non-cell-autonomous mechanisms required for the development of hamartomas in patients with TSC. Future approaches using this model system will include investigation of key genetic interactions and screening for compounds that can modulate TOR-dependent and -independent signaling pathways.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0), which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the original work is properly cited and all further distributions of the work or adaptation are subject to the same Creative Commons License terms.