Heterozygosity for the tuberous sclerosis complex (TSC) gene products results in increased astrocyte numbers and decreased p27-Kip1 expression in TSC2+/− cells

Uhlmann, Erik J.; Apicelli, Anthony J.; Baldwin, Rebecca L.; Burke, Stephen P.; Bajenaru, M. L.; Onda, Hiroaki; Kwiatkowski, David J.; Gutmann, David H.

doi:10.1038/sj.onc.1205435

Cited by 76 publications

(78 citation statements)

References 45 publications

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“…The corresponding mouse models with mutations in MeCP2, FMR1, TSC1/TSC2, or NF1 exhibit certain behavioral and morphological changes that are reminiscent of ASCs (16)(17)(18)(19)(20)(21)(22)(23)(24)(25). The same is true for mice in which a limited number of cortical and hippocampal neurons lack the lipid phosphatase PTEN (26), which is functionally linked to TSC2 and mutated in some individuals with ASC (27,28).…”

Section: Discussionmentioning

confidence: 95%

Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism

Jamain

Radyushkin

Hammerschmidt

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

518

456

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Autism spectrum conditions (ASCs) are heritable conditions characterized by impaired reciprocal social interactions, deficits in language acquisition, and repetitive and restricted behaviors and interests. In addition to more complex genetic susceptibilities, even mutation of a single gene can lead to ASC. Several such monogenic heritable ASC forms are caused by loss-of-function mutations in genes encoding regulators of synapse function in neurons, including NLGN4. We report that mice with a loss-of-function mutation in the murine NLGN4 ortholog Nlgn4, which encodes the synaptic cell adhesion protein Neuroligin-4, exhibit highly selective deficits in reciprocal social interactions and communication that are reminiscent of ASCs in humans. Our findings indicate that a protein network that regulates the maturation and function of synapses in the brain is at the core of a major ASC susceptibility pathway, and establish Neuroligin-4-deficient mice as genetic models for the exploration of the complex neurobiological disorders in ASCs.behavior ͉ neuroligin ͉ synaptogenesis

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Section: Discussionmentioning

confidence: 95%

Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism

Jamain

Radyushkin

Hammerschmidt

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

518

456

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“…It has been shown that the loss of tuberin or hamartin triggers p27 protein down-regulation in vivo. Astrocytes and fibroblasts of TSC1ϩ/Ϫ or TSC2ϩ/Ϫ mice as well as astrocytes of astrocyte-specific TSC1 conditional knock-out mice exhibit decreased p27 expression (27,28). Investigations of the localization of p27 in TSC-associated lesions are still missing.…”

Section: Discussionmentioning

confidence: 99%

Tuberin Binds p27 and Negatively Regulates Its Interaction with the SCF Component Skp2

Rosner

Hengstschläger

2004

Journal of Biological Chemistry

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TSC1 (tuberous sclerosis complex 1) encoding hamartin and TSC2 encoding tuberin are tumor suppressor genes responsible for the autosomal dominantly inherited disease tuberous sclerosis. These genes have been demonstrated to negatively regulate cell cycle progression, the activity of cdk2, and the degradation of the cyclin-dependent kinase inhibitor p27. To date, the underlying molecular mechanism remains elusive. Here, we show that tuberin binds to p27. Whereas tuberin also binds p27 in TSC1-negative cells, hamartin does not bind p27 without tuberin. p27 protein levels are regulated through ubiquitin-dependent degradation. Skp2 is the F-box protein, which, together with other proteins, forms an SCF (Skp1/cullin/F-box protein)-type E3 ubiquitin ligase complex whose task is to target p27 for degradation by the proteasome. We found that neither tuberin nor hamartin are in a complex with Skp2. Tuberin does not affect Skp2 protein levels, and the SCF Skp2 ubiquitin ligase does not regulate tuberin stability. But binding of tuberin to p27 sequesters p27 from Skp2 accompanied by an up-regulation of the p27 interaction with cdk2. Skp2-induced p27 degradation and cell cycle progression is abolished by tuberin s protective binding to p27. This work, the first description of the direct interaction of a tumor suppressor protein with p27, provides a molecular explanation for the effects of tuberous sclerosis complex genes on the cell cycle and demonstrates a new aspect of the SCF Skp2 -mediated regulation of p27 stability.

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“…These mice do not exhibit a clear phenotype of TSC central nervous system involvement, except that altered ultrasonic vocalizations that suggest social abnormalities have been reported in Tsc2+/− mice [106]. In the central nervous system of Tsc2+/− and Tsc1+/− mice, the number of astrocytes is increased, which suggests that hamartin and tuberin are important astrocyte growth regulators [107]. These findings, and the frequent development of astrocytic tumors in patients with TSC, highlight the importance of astrocytes in the involvement of TSCs with the brain.…”

Section: Tuberous Sclerosis Complexmentioning

confidence: 93%

Novel Animal Models of Pediatric Epilepsy

et al. 2012

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When mimicking epileptic processes in a laboratory setting, it is important to understand the differences between experimental models of seizures and epilepsy. Because human epilepsy is defined by the appearance of multiple spontaneous recurrent seizures, the induction of a single acute seizure without recurrence does not constitute an adequate epilepsy model. Animal models of epilepsy might be useful for various tasks. They allow for the investigation of pathophysiological mechanisms of the disease, the evaluation, or the development of new antiepileptic treatments, and the study of the consequences of recurrent seizures and neurological and psychiatric comorbidities. Although clinical relevance is always an issue, the development of models of pediatric epilepsies is particularly challenging due to the existence of several key differences in the dynamics of human and rodent brain maturation. Another important consideration in modeling pediatric epilepsy is that "children are not little adults," and therefore a mere application of models of adult epilepsies to the immature specimens is irrelevant. Herein, we review the models of pediatric epilepsy. First, we illustrate the differences between models of pediatric epilepsy and models of the adulthood consequences of a precipitating insult in early life. Next, we focus on new animal models of specific forms of epilepsies that occur in the developing brain. We conclude by emphasizing the deficiencies in the existing animal models and the need for several new models.

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Heterozygosity for the tuberous sclerosis complex (TSC) gene products results in increased astrocyte numbers and decreased p27-Kip1 expression in TSC2+/− cells

Cited by 76 publications

References 45 publications

Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism

Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism

Tuberin Binds p27 and Negatively Regulates Its Interaction with the SCF Component Skp2

Novel Animal Models of Pediatric Epilepsy

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