Astrocyte‐specific <i>TSC1</i> conditional knockout mice exhibit abnormal neuronal organization and seizures

Uhlmann, Erik J.; Wong, Michael; Baldwin, Rebecca L.; Bajenaru, M. L.; Onda, Hiroaki; Kwiatkowski, David J.; Yamada, Kelvin A.; Gutmann, David H.

doi:10.1002/ana.10283

Cited by 327 publications

(396 citation statements)

References 42 publications

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“…Additionally, epilepsy, brain malformations, RCCs and additional tumors have been described in Eker rats, which have a naturally occurring inactivating Tsc2 mutation (Cook and Walker, 2004;Hino, 2004;Yeung, 2004). Epilepsy and brain abnormalities were also detected in mice with a specific Tsc1 deletion in cells of the neuronal system (Uhlmann et al, 2002).…”

Section: Nf1mentioning

confidence: 99%

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

et al. 2011

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The liver kinase B1 (LKB1)/adenosine mono-phosphateactivated protein kinase (AMPK)/tuberous sclerosis complex (TSC)/mammalian target of rapamycin (mTOR) complex (mTORC1) cassette constitutes a canonical signaling pathway that integrates information on the metabolic and nutrient status and translates this into regulation of cell growth. Alterations in this pathway are associated with a wide variety of cancers and hereditary hamartoma syndromes, diseases in which hyperactivation of mTORC1 has been described. Specific mTORC1 inhibitors have been developed for clinical use, and these drugs have been anticipated to provide efficient treatment for these diseases. In the present review, we provide an overview of the metabolic LKB1/AMPK/TSC/mTORC1 pathway, describe how its aberrant signaling associates with cancer development, and indicate the difficulties encountered when biochemical data are extrapolated to provide avenues for rational treatment of disease when targeting this signaling pathway. A careful examination of preclinical and clinical studies performed with rapamycin or derivatives thereof shows that although results are encouraging, we are only half way in the long and winding road to design rationale treatment targeted at the LKB1/ AMPK/TSC/mTORC1 pathway. Inherited cancer syndromes associated with this pathway such as the PeutzJeghers syndrome and TSC, provide perfect models to study the relationship between genetics and disease phenotype, and to delineate the complexities that underlie translation of biochemical and genetical information to clinical management, and thus provide important clues for devising novel rational medicine for cancerous diseases in general.

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Section: Nf1mentioning

confidence: 99%

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

et al. 2011

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“…Tsc1 GFAP CKO mice were generated as previously described 26 at the Washington University School of Medicine in accordance with the guidelines established by the Animal Studies Committee of Washington University.…”

Section: Tsc1 Gfap Cko Micementioning

confidence: 99%

“…Of note, GFAP mRNA expression in the cortex was increased by 3.8-fold at postnatal day 1 and 6.4-fold at postnatal day 10, consistent with previous reports that there is progressive increase in the number of astrocytes in the Tsc1 GFAP CKO mice. 26 …”

Section: Increased Growth Factor Mrna Expression In Tsc1 Gfap Cko Micementioning

confidence: 99%

Enhanced Epidermal Growth Factor, Hepatocyte Growth Factor, and Vascular Endothelial Growth Factor Expression in Tuberous Sclerosis Complex

Parker

Orlova

Heuer

et al. 2011

The American Journal of Pathology

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Epidermal growth factor (EGF), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF) regulate angiogenesis and cell growth in the developing brain. EGF, HGF, and VEGF modulate the activity of the mammalian target of rapamycin (mTOR) cascade, a pathway regulating cell growth that is aberrantly activated in tuberous sclerosis complex (TSC). We hypothesized that expression of EGF, HGF, VEGF, and their receptors EGFR, c-Met, and Flt-1, respectively, would be altered in TSC. We show by cDNA array and immunohistochemical analysis that EGF, EGFR, HGF, c-Met, and VEGF, but not Flt-1, mRNA, and protein expression was up-regulated in Tsc1 conditional knockout (Tsc1 GFAP CKO) mouse cortex. Importantly, these alterations closely predicted enhanced expression of these proteins in tuber and subependymal giant cell astrocytoma (SEGA) specimens in TSC. Expression of EGF, EGFR, HGF, c-Met, and VEGF protein, as well as hypoxia inducible factor-1␣, a transcription factor that regulates VEGF levels and is also modulated by mTOR cascade activity, was enhanced in SEGAs (n ‫؍‬ 6) and tubers (n ‫؍‬ 10) from 15 TSC patients. Enhanced expression of these growth factors and growth factor receptors in human SEGAs and tubers and in the Tsc1 GFAP CKO mouse may account for enhanced cellular growth and proliferation in tubers and SEGAs and provides potential target molecules for therapeutic development in TSC. Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that results from mutations in the TSC1 or TSC2 genes, which encode TSC1 and TSC2 proteins, respectively. 1,2 Many individuals with TSC exhibit cognitive disability and autism, 3 and more than 75% of TSC patients develop seizures. 4 -6 Examination of the brain demonstrates cortical tubers and subependymal nodules (SENs) in more than 70% of TSC patients. Tubers are developmental malformations of the cerebral cortex highly associated with epilepsy and neurocognitive abnormalities. SENs are nodular lesions (typically smaller than 1 cm) located on the surfaces of the lateral and third ventricles. In approximately 10% to 20% of TSC patients, subependymal giant cell astrocytomas (SEGAs) arise within the lateral ventricles, often near the foramen of Monro. SEGAs are World Health Organization grade I tumors with low mitotic index as evidenced by Ki-67 immunoreactivity suggestive of slow cellular proliferation. 7,8 It is widely believed that SENs grow to form SEGAs, although the molecular mechanisms governing transformation from SEN to SEGA are unknown. 9 Both SENs and SEGAs consist of dysmorphic glial cells, enlarged giant cells (GCs), and spindle-shaped cells of unknown phenotype. 10,11 Cellular immunoreactivity for glial fibrillary acidic protein (GFAP), neurofilament, S-100, neuron-specific enoSupported by NS045877, NS045021, and Department of Defense CDMRP-TSC Program grants (P.B.C.); the National Epilepsy Fund -"Power of the Small," Hersenstichting Nederland (NEF 02-10 and NEF 05-11) and Stichting Michelle (M06.011) (E.A.); and AOA and AANS medical s...

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“…Recent evidence suggests that loss of function mutations in the tuberous sclerosis complex genes (TSC1 and TSC2) leads to constitutive activation of the mTOR cascade (Arrazola et al, 2002;Inoki et al, 2002;Kenerson et al, 2002;Onda et al, 2002, Tee et al, 2002, El-Hashemite et al, 2003 and disturbs the regulation of neuronal morphology and function mediated by TSC1 and TSC2 (Tavazoie et al, 2005) resulting in abnormal neuronal organization and seizures (Uhlmann et al, 2002). Rapamycin has been proposed as a treatment modality for tuberous sclerosis complex (TSC), a multisystem, autosomal dominant disorder characterized by abnormal brain development, epilepsy, and potentially life threatening disorders such as pulmonary lymphangioleimyomatosis (Johnson and Tattersfield, 2002;Crino et al, 2006) Rapamycin is a potent translational modifier in neurons although its effects on gene transcription and neuronal development are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Effects of rapamycin on gene expression, morphology, and electrophysiological properties of rat hippocampal neurons

et al. 2007

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SummaryPurpose-We assayed the effects of rapamycin, an immunomodulatory agent known to inhibit the activity of the mammalian target of rapamycin (mTOR) cascade, on candidate gene expression and single unit firing properties in cultured rat hippocampal neurons as a strategy to define the effects of rapamycin on neuronal gene transcription and excitability.Methods-Rapamycin was added (100 nM) to cultured hippocampal neurons on days 3 and 14. Neuronal somatic size and dendritic length were assayed by immunohistochemistry and digital imaging. Radiolabeled mRNA was amplified from single hippocampal pyramidal neurons and used to probe cDNA arrays containing over 100 distinct candidate genes including cytoskeletal element, growth factor, transcription factor, neurotransmitter, and ion channel genes. In addition, the effects of rapamycin (200 nM) on spontaneous neuronal activity and voltage-dependent currents was assessed.Results-There were no effects of rapamycin on cell size or dendrite length. Rapamycin altered expression of distinct mRNAs in each gene family on days 3 and 14 in culture. Single unit recordings from neurons exposed to rapamycin exhibited no change from baseline. When spontaneous activity was increased by blocking GABA-mediated inhibition with bicuculline, a fraction of the neurons exhibited a decreased duration of spontaneous bursts and a decrease in synaptic inputs. Rapamycin did not appear to alter voltage dependent Na+ or K+ currents underlying action potentials.Conclusions-These data demonstrate that rapamycin does not produce neurotoxicity nor alter dendritic growth and complexity in vitro and does not significantly alter voltage gated sodium and potassium currents. Rapamycin does affect neuronal gene transcription in vitro. Use of rapamycin in clinical trials for patients with tuberous sclerosis complex should involve vigilance for possible effects on seizure frequency and neurocognitive function.

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Astrocyte‐specific TSC1 conditional knockout mice exhibit abnormal neuronal organization and seizures

Cited by 327 publications

References 42 publications

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

Enhanced Epidermal Growth Factor, Hepatocyte Growth Factor, and Vascular Endothelial Growth Factor Expression in Tuberous Sclerosis Complex

Effects of rapamycin on gene expression, morphology, and electrophysiological properties of rat hippocampal neurons

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