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General Comment |
This gene encodes a growth inhibitory protein thought to play a role in the stabilization of tuberin. Mutations in this gene have been associated with tuberous sclerosis. Alternative splicing results in multiple transcript variants.
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Promotion of Ovarian Follicle Growth following mTOR Activation: Synergistic Effects of AKT Stimulators. Cheng Y et al. (2015) Mammalian target of rapamycin (mTOR) is a serine/threonine kinase and mTOR signaling is important in regulating cell growth and proliferation. Recent studies using oocyte- and granulosa cell-specific deletion of mTOR inhibitor genes TSC1 or TSC2 demonstrated the important role of mTOR signaling in the promotion of ovarian follicle development. We now report that treatment of ovaries from juvenile mice with an mTOR activator MHY1485 stimulated mTOR, S6K1 and rpS6 phosphorylation. Culturing ovaries for 4 days with MHY1485 increased ovarian explant weights and follicle development. In vivo studies further demonstrated that pre-incubation of these ovaries with MHY1485 for 2 days, followed by allo-grafting into kidney capsules of adult ovariectomized hosts for 5 days, led to marked increases in graft weights and promotion of follicle development. Mature oocytes derived from MHY1485-activated ovarian grafts could be successfully fertilized, leading the delivery of healthy pups. We further treated ovaries with the mTOR activator together with AKT activators (PTEN inhibitor and phosphoinositol-3-kinase stimulator) before grafting and found additive enhancement of follicle growth. Our studies demonstrate the ability of an mTOR activator in promoting follicle growth, leading to a potential strategy to stimulate preantral follicle growth in infertile patients.//////////////////
Tuberous sclerosis complex (TSC) is a dominantly inherited disease of high penetrance, characterized pathologically by
the presence of hamartomata in multiple organ systems. Well known clinical manifestations include epilepsy, learning
difficulties, behavioral problems, and skin lesions. Many patients have renal lesions, usually angiomyolipomata, which
can cause clinical problems secondary to hemorrhage or by compression and replacement of healthy renal tissue, which
rarely causes end-stage renal failure. Cysts, polycystic renal disease, and renal carcinoma can also occur.
Xiao et al. (1997) reported that tuberin exhibits substantial GAP activity towards RAB5 , a critical and
rate-limiting component of the docking and fusion process of the endocytic pathway. An intermediate adaptor-like molecule,
rabaptin-5 , mediates the tuberin association with RAB5. The authors suggested that tuberin functions as a
RAB5GAP in vivo to regulate RAB5-GTP activity negatively in endocytosis. They speculated that loss of the RAB5GAP
activity encoded by the tumor suppressor gene TSC2 might interfere with the endocytic pathway, leading to missorting of
internalized growth factor receptors or other molecules that would otherwise undergo lysosomal degradation.Hamartin, the protein that is defective in TSC1, has no significant homology to tuberin or any other
known vertebrate protein. Van Slegtenhorst et al. (1998) showed that hamartin and tuberin associate physically in vivo,
however, and that the interaction is mediated by predicted coiled-coil domains. The data suggested to the authors that
hamartin and tuberin function in the same complex rather than in separate pathways.
NCBI Summary:
This gene is a tumor suppressor gene that encodes the growth inhibitory protein hamartin. The encoded protein interacts with and stabilizes the GTPase activating protein tuberin. This hamartin-tuberin complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signalling which is a major regulator of anabolic cell growth. This protein also functions as a co-chaperone for Hsp90 that inhibits its ATPase activity. This protein functions as a facilitator of Hsp90-mediated folding of kinase and non-kinase clients, including Tsc2 and thereby preventing their ubiquitination and proteasomal degradation. Mutations in this gene have been associated with tuberous sclerosis. [provided by RefSeq, Apr 2018]
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Comment |
microRNA 92b-3p regulates primordial follicle assembly by targeting TSC1 in neonatal mouse ovaries. Li T et al. (2019) The primordial follicle pool, providing all oocytes available to a female throughout her reproductive life, is established perinatally. The formation of primordial follicle pool is regulated by precise transcriptional and post-transcriptional mechanisms. Recent studies have identified several microRNAs as post-transcriptional regulatory factors in the process of primordial follicle assembly. Here, we showed that miR-92b-3p was significantly upregulated in the stage of primordial follicle assembly in newborn mouse ovaries. Inhibiting miR-92b-3p suppressed the formation of primordial follicles, while overexpression of miR-92b-3p accelerated the processes of cyst breakdown and the following primordial follicle assembly. Accordingly, the expression of follicular development-related genes was reduced upon inhibiting of miR-92b-3p, and increased under miR-92b-3p overexpression. Mechanistic studies identified TSC1 as a direct target of miR-92b-3p. miR-92b-3p could activate mTOR/Rps6 signaling through targeting and inhibiting TSC1 expression. In addition, knockdown of TSC1 showed an identical phenotype with that of miR-92b-3p overexpression in accelerating processes of cyst breakdown and primordial follicle formation. Thus, our work demonstrates that miR-92b-3p is a novel regulator of primordial follicle assembly by negatively regulating TSC1 in mTOR/Rps6 signaling.//////////////////
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Comment |
Fukuda T,et al 2000 reported the distribution of Tsc1 protein detected by
immunohistochemistry in various normal rat tissues. It was previously demonstrated that
hereditary mutation and a subsequent second hit in the rat homolog of tuberous sclerosis
gene (Tsc2) are responsible for Eker renal carcinomas (RC). In humans, alteration in the
TSC2 gene is known to cause the tuberous sclerosis complex (TSC) that results in
hamartomatous lesions in multiple organs, but the function of TSC2 is not fully
understood. In recent years, a second gene (TSC1) responsible for human TSC has been
cloned, and binding between TSC1 and TSC2 proteins was reported. To clarify
associations between Tsc proteins in vivo, the expression of Tsc1 protein was detected
by immunohistochemistry, and compared with Tsc2 expression. Tsc1 protein was
expressed in the nervous system and in many endocrine tissues, including pancreatic
islets, the parathyroids, testis, and ovary.
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Mutations |
3 mutations
Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Deletion of Tuberous Sclerosis 1 in Somatic Cells of the Murine Reproductive Tract Causes Female Infertility. Tanaka Y et al. Tumors develop with dysregulated activation of mammalian target of rapamycin (mTOR), the kinase activity of which is kept in an inactive state by a tumor suppressor dimer containing tuberous sclerosis 1 (TSC1) and TSC2. We examined whether conditional deletion of TSC1 by a knock-in allele of the anti-M?an hormone type 2 receptor (Amhr2) driving Cre expression and subsequent activation of mTOR in granulosa cells and in oviductal and uterine stromal cells affects fertility in female mice. Increased phosphorylation of ribosomal protein S6, a downstream target of activated mTOR, was observed in all AMHR2-expressing tissues examined, indicating loss of TSC1 activity. TSC1 deletion in granulosa cells led to the detection of significantly fewer primordial follicles in mutant mice at 12 wk, suggesting premature ovarian insufficiency, which might be related to the significantly increased time mutant mice spent in estrus. Although the number of good-quality ovulated oocytes was not significantly different compared with controls, there was a significantly higher number of degenerated oocytes after normal and superovulation, suggesting compromised oocyte quality, as well. Natural mating also showed severalfold higher numbers of degenerate bodies in the mutants that collected in bilateral swellings resembling hydrosalpinges that formed in all mice examined because of occlusion of the proximal oviduct. Attempts to transfer control embryos into mutant uteri also failed, indicating that implantation was compromised. Endometrial epithelial cells continued to proliferate, and quantitative RT-PCR showed that mucin 1 expression persisted during the window of implantation in mutant uteri, without any changes in progesterone receptor mRNA expression, suggesting a mechanism that does not involve disrupted estradiol-regulated progesterone receptor expression. Homozygous deletion of TSC1 in reproductive tract somatic tissues of mice rendered females completely infertile, which is likely due to these pleiotropic effects on follicle recruitment, oviductal development, and blastocyst implantation.
Species: mouse
Mutation name: None
type: null mutation
fertility: fertile
Comment: Specific Disruption of Tsc1 in Ovarian Granulosa Cells Promotes Ovulation and Causes Progressive Accumulation of Corpora Lutea. Huang L et al. Tuberous sclerosis complex 1 (Tsc1) is a tumor suppressor negatively regulating mammalian target of rapamycin complex 1 (mTORC1). It is reported that mice lacking Tsc1 gene in oocytes show depletion of primordial follicles, resulting in premature ovarian failure and subsequent infertility. A recent study indicated that deletion of Tsc1 in somatic cells of the reproductive tract caused infertility of female mice. However, it is not known whether specific disruption of Tsc1 in granulosa cells influences the reproductive activity of female mice. To clarify this problem, we mated Tsc1(flox/flox) mice with transgenic mice strain expressing cyp19-cre which exclusively expresses in granulosa cells of the ovary. Our results demonstrated that Tsc1(flox/flox); cyp19-cre mutant mice were fertile, ovulating more oocytes and giving birth to more pups than control Tsc1(flox/flox) mice. Progressive accumulation of corpora lutea occurred in the Tsc1(flox/flox); cyp19-cre mutant mice with advanced age. These phenotypes could be explained by the elevated activity of mTORC1, as indicated by increased phosphorylation of rpS6, a substrate of S6 in the Tsc1(flox/flox); cyp19-cre mutant granulosa cells. In addition, rapamycin, a specific mTORC1 inhibitor, effectively rescued the phenotype caused by increased mTORC1 activity in the Tsc1(cko) ovaries. Our data suggest that conditional knockout of Tsc1 in granulosa cells promotes reproductive activity in mice.
Species: mouse
Mutation name: None
type: null mutation
fertility: subfertile
Comment: Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles. Adhikari D 2009 et al.
To maintain the female reproductive lifespan, the majority of ovarian primordial follicles are preserved in a quiescent state in order to provide ova for later reproductive life. However, the molecular mechanism that maintains the long quiescence of primordial follicles is poorly understood. Here we provide genetic evidence to show that the tumor suppressor tuberous sclerosis complex 1 (Tsc1), which negatively regulates mammalian target of rapamycin complex 1 (mTORC1), functions in oocytes to maintain the quiescence of primordial follicles. In mutant mice lacking the Tsc1 gene in oocytes, the entire pool of primordial follicles is activated prematurely due to elevated mTORC1 activity in the oocyte, ending up with follicular depletion in early adulthood and causing premature ovarian failure (POF). We further show that maintenance of the quiescence of primordial follicles requires synergistic, collaborative functioning of both Tsc and PTEN (phosphatase and tensin homolog deleted on chromosome 10) and that these two molecules suppress follicular activation through distinct ways. Our results suggest that Tsc/mTORC1 signaling and PTEN/PI3K (phosphatidylinositol 3 kinase) signaling synergistically regulate the dormancy and activation of primordial follicles, and together ensure the proper length of female reproductive life. Deregulation of these signaling pathways in oocytes results in pathological conditions of the ovary, including POF and infertility.
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