ArticleHuman molecular genetics2009
A hypomorphic allele of Tsc2 highlights the role of TSC1/TSC2 in signaling to AKT and models mild human TSC2 alleles.
Article in Human molecular genetics, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 34 citations in OpenAlex.
- Neuronal hyperactivity becomes mTORC1 independent due to transcriptional changes in tuberous sclerosis complex disease models.Cell reports · 2025Article
- Gene replacement therapies for inherited disorders of neurotransmission: Current progress in succinic semialdehyde dehydrogenase deficiency.Journal of inherited metabolic disease · 2024Review
- Targeting the PI3K/AKT/mTOR and RAF/MEK/ERK pathways for cancer therapy.Molecular biomedicine · 2022Review
- A multi‑omics study of diagnostic markers and the unique inflammatory tumor micro‑environment involved in tuberous sclerosis complex‑related renal angiomyolipoma.International journal of oncology · 2022Article
- Factors influencing the acute pentylenetetrazole-induced seizure paradigm and a literature review.Annals of clinical and translational neurology · 2021Review
- TrkB hyperactivity contributes to brain dysconnectivity, epileptogenesis, and anxiety in zebrafish model of Tuberous Sclerosis Complex.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- mGluR5 Modulation of Behavioral and Epileptic Phenotypes in a Mouse Model of Tuberous Sclerosis Complex.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2018Article
- Functional kinomics establishes a critical node of volume-sensitive cation-ClScientific reports · 2016Article
- Lkb1 deletion upregulates Pax7 expression through activating Notch signaling pathway in myoblasts.The international journal of biochemistry & cell biology · 2016Article
- Serine 302 Phosphorylation of Mouse Insulin Receptor Substrate 1 (IRS1) Is Dispensable for Normal Insulin Signaling and Feedback Regulation by Hepatic S6 Kinase.The Journal of biological chemistry · 2016Article
- A murine model of neurofibromatosis type 2 that accurately phenocopies human schwannoma formation.Human molecular genetics · 2015Article
- The neural crest lineage as a driver of disease heterogeneity in Tuberous Sclerosis Complex and Lymphangioleiomyomatosis.Frontiers in cell and developmental biology · 2014Review
- mTORC1 enhancement of STIM1-mediated store-operated Ca2+ entry constrains tuberous sclerosis complex-related tumor development.Oncogene · 2013Article
- Graded loss of tuberin in an allelic series of brain models of TSC correlates with survival, and biochemical, histological and behavioral features.Human molecular genetics · 2012Article
- Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth.Proceedings of the National Academy of Sciences of the United States of America · 2011Article
- Deletion of Lkb1 in pro-opiomelanocortin neurons impairs peripheral glucose homeostasis in mice.Diabetes · 2011Article
- Animal models of lymphangioleiomyomatosis (LAM) and tuberous sclerosis complex (TSC).Lymphatic research and biology · 2010Review
- Lymphangioleiomyomatosis and TSC2-/- cells.Lymphatic research and biology · 2010Review
- Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade.The Journal of clinical investigation · 2010Article
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7 authors at 1 institution in 1 country.
Funding
Abstract
Tuberous sclerosis complex (TSC) is a tumor suppressor gene syndrome in which hamartomas develop in multiple organ systems. Knockout and conditional alleles of Tsc1 and Tsc2 have been previously reported. Here, we describe the generation of a novel hypomorphic allele of Tsc2 (del3), in which exon 3, encoding 37 amino acids near the N terminus of tuberin, is deleted. Embryos homozygous for the del3 allele survive until E13.5, 2 days longer than Tsc2 null embryos. Embryos die from underdevelopment of the liver, deficient hematopoiesis, aberrant vascular development and hemorrhage. Mice that are heterozygous for the del3 allele have a markedly reduced kidney tumor burden in comparison with conventional Tsc2(+/-) mice. Murine embryo fibroblast (MEF) cultures that are homozygous for the del3 allele express mutant tuberin at low levels, and show enhanced activation of mTORC1, similar to Tsc2 null MEFs. Furthermore, the mutant cells show prominent reduction in the activation of AKT. Similar findings were made in the analysis of homozygous del3 embryo lysates. Tsc2-del3 demonstrates GTPase activating protein activity comparable to that of wild-type Tsc2 in a functional assay. These findings indicate that the del3 allele is a hypomorphic allele of Tsc2 with partial function due to reduced expression, and highlight the consistency of AKT downregulation when Tsc1/Tsc2 function is reduced. Tsc2-del3 mice also serve as a model for hypomorphic TSC2 missense mutations reported in TSC patients.
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