ArticleHuman molecular genetics2012
Graded loss of tuberin in an allelic series of brain models of TSC correlates with survival, and biochemical, histological and behavioral features.
Article in Human molecular genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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38 citing papers in PubMed, 58 citations in OpenAlex.
- Impaired nuclear PTEN function drives macrocephaly, lymphadenopathy and late-onset cancer in PTEN hamartoma tumour syndrome.Disease models & mechanisms · 2026Article
- Neuronal hyperactivity becomes mTORC1 independent due to transcriptional changes in tuberous sclerosis complex disease models.Cell reports · 2025Article
- Early death and neuronal abnormalities inbioRxiv : the preprint server for biology · 2025Article
- Larp1 supports brain growth and spatial memory via post-transcriptional control of the translation machinery.bioRxiv : the preprint server for biology · 2025Article
- Phenotypic rescue via mTOR inhibition in neuron-specific Pten knockout mice reveals AKT and mTORC1-site specific changes.Molecular psychiatry · 2025Article
- Neuropsychiatric disorders in Chinese pediatric tuberous sclerosis complex patients associated with drug-resistant epilepsy: A TAND checklist-based survey.Epilepsy & behavior reports · 2025Article
- Focal postnatal deletion ofFrontiers in molecular neuroscience · 2025Article
- Developmental trajectories of GABAergic cortical interneurons are sequentially modulated by dynamicProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Using cortical organoids to understand the pathogenesis of malformations of cortical development.Frontiers in neuroscience · 2024Review
- Seizure reduction in TSC2-mutant mouse model by an mTOR catalytic inhibitor.Annals of clinical and translational neurology · 2023Article
- Proteomics analysis of prefrontal cortex of Alzheimer's disease patients revealed dysregulated proteins in the disease and novel proteins associated with amyloid-β pathology.Cellular and molecular life sciences : CMLS · 2023Article
- DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting.Cell reports · 2022Article
- mTOR inhibitor improves autistic-like behaviors related to Tsc2 haploinsufficiency but not following developmental status epilepticus.Journal of neurodevelopmental disorders · 2021Article
- Inhibition of mTOR signaling by genetic removal of p70 S6 kinase 1 increases anxiety-like behavior in mice.Translational psychiatry · 2021Article
- Biallelic Mutations inThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2019Article
- GATORopathies: The role of amino acid regulatory gene mutations in epilepsy and cortical malformations.Epilepsia · 2019Review
- Inactivation ofAmerican journal of physiology. Renal physiology · 2019Article
- Chronic mTORC1 inhibition rescues behavioral and biochemical deficits resulting from neuronal Depdc5 loss in mice.Human molecular genetics · 2019Article
- Inhibition of the glutamine transporter SNAT1 confers neuroprotection in mice by modulating the mTOR-autophagy system.Communications biology · 2019Article
- A novel mouse model of hemangiopericytoma due to loss of Tsc2.Human molecular genetics · 2018Article
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder with prominent brain manifestations due to mutations in either TSC1 or TSC2. Here, we describe novel mouse brain models of TSC generated using conditional hypomorphic and null alleles of Tsc2 combined with the neuron-specific synapsin I cre (SynIcre) allele. This allelic series of homozygous conditional hypomorphic alleles (Tsc2(c-del3/c-del3)SynICre(+)) and heterozygote null/conditional hypomorphic alleles (Tsc2(k/c-del3)SynICre(+)) achieves a graded reduction in expression of Tsc2 in neurons in vivo. The mice demonstrate a progressive neurologic phenotype including hunchback, hind limb clasp, reduced survival and brain and cortical neuron enlargement that correlates with a graded reduction in expression of Tsc2 in the two sets of mice. Both models also showed behavioral abnormalities in anxiety, social interaction and learning assays, which correlated with Tsc2 protein levels as well. The observations demonstrate that there are graded biochemical, cellular and clinical/behavioral effects that are proportional to the extent of reduction in Tsc2 expression in neurons. Further, they suggest that some patients with milder manifestations of TSC may be due to persistent low-level expression of functional protein from their mutant allele. In addition, they point to the potential clinical benefit of strategies to raise TSC2 protein expression from the wild-type allele by even modest amounts.
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