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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

Oncogene volume 21, pages 4050–4059 (2002)Cite this article

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant tumor predisposition syndrome characterized by benign proliferations (hamartomas). In the brain, individuals with TSC develop autism, mental retardation and seizures associated with focal cortical dysplasias, subependymal nodules, and subependymal giant cell astrocytomas (SEGAs). We hypothesize that dysregulated astrocyte function due to mutations in the tumor suppressor genes, TSC1 and TSC2, may contribute to the pathogenesis of these brain abnormalities. In this report, we demonstrate that mice heterozygous for a targeted defect in either the Tsc1 or Tsc2 genes(Tsc1+/− and Tsc2+/− mice) exhibit a 1.5-fold increase in the number of astrocytes in vivo. Whereas increased astrocyte numbers in vivo were suggestive of a proliferative advantage, Tsc2+/− primary astrocyte cultures did not show a cell-autonomous growth advantage, anchorage-independent growth, increased saturation density, or increased fluid-phase endocytosis compared to wild type astrocytes. Tsc2 null mouse embryonic fibroblasts (MEFs) however, did exhibit increased saturation density compared to Tsc2 wild type controls. In both Tsc2+/− astrocytes and Tsc2 null mouse embryonic fibroblasts, p27-Kip1 expression was decreased compared to wild type cells, and was reversed by tuberin re-expression in Tsc2−/− MEFs. In contrast, no change in endocytosis was observed upon tuberin re-expression in Tsc2−/− MEFs. Collectively, these results suggest Tsc heterozygosity may provide a non-cell-autonomous growth advantage for astrocytes that may involve p27-Kip1 expression.

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Acknowledgements

We appreciate the helpful discussions and suggestions provided by Drs Gerry Boss, Peter Crino and Philip Stahl during the execution of these experiments. This work was supported by generous funding from the Tuberous Sclerosis Alliance Center without Walls initiative (to DH Gutmann and D Kwiatkowski) and NIH grant NS31535 (to D Kwiatkowski). ML Bajenaru was supported by a fellowship from the National Tuberous Sclerosis Association.

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  1. Department of Neurology, Washington University School of Medicine, St Louis, Missouri, USA

    Erik J Uhlmann, Anthony J Apicelli, Rebecca L Baldwin, Stephen P Burke, M Livia Bajenaru & David H Gutmann

  2. Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Hiroaki Onda & David Kwiatkowski

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  1. Erik J Uhlmann
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  2. Anthony J Apicelli
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Correspondence to David H Gutmann.

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Uhlmann, E., Apicelli, A., Baldwin, R. et al. Heterozygosity for the tuberous sclerosis complex (TSC) gene products results in increased astrocyte numbers and decreased p27-Kip1 expression in TSC2+/− cells. Oncogene 21, 4050–4059 (2002). https://doi.org/10.1038/sj.onc.1205435

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