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Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease

Nature Genetics volume 29, pages 396–403 (2001)Cite this article

Abstract

Initially identified in high-grade gliomas, mutations in the PTEN tumor-suppressor are also found in many sporadic cancers and a few related autosomal dominant hamartoma syndromes. PTEN is a 3′-specific phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) phosphatase and functions as a negative regulator of PI3K signaling. We generated a tissue-specific deletion of the mouse homolog Pten to address its role in brain function. Mice homozygous for this deletion (PtenloxP/loxP;Gfap-cre), developed seizures and ataxia by 9 wk and died by 29 wk. Histological analysis showed brain enlargement in PtenloxP/loxP;Gfap-cre mice as a consequence of primary granule-cell dysplasia in the cerebellum and dentate gyrus. Pten mutant cells showed a cell-autonomous increase in soma size and elevated phosphorylation of Akt. These data represent the first evidence for the role of Pten and Akt in cell size regulation in mammals and provide an animal model for a human phakomatosis condition, Lhermitte-Duclos disease (LDD).

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Figure 1: Targeted conditional deletion of Pten in the brain.
Figure 2: Pten expression in glial cells of PtenloxP/loxP;Gfap-cre mice aged 10 wk.
Figure 7: Pronounced dysplasia of the dentate gyrus (DG) and CA3.
Figure 3: Brain-specific conditional deletion of Pten results in premature death, macrocephaly and hydrocephalus.
Figure 4: Staining of cerebella of PtenloxP/loxP;Gfap-cre mice and controls.
Figure 5: Increased activation of Akt and granule soma size in PtenloxP/loxP;Gfap-cre cerebella.
Figure 6: Appearance, cell death and proliferation are normal in the EGCL of Pten mutant mice during postnatal development.

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Acknowledgements

We thank S. Baker for providing Gfap-cre mice and discussing data before publication, K. So, L. Yoong, S. Plyte, W. King, J. Henderson and J. Robertson for technical assistance and S. Pownall, A. Guha and M. Burnham for helpful comments and discussion. V.S. is a recipient of a postdoctoral fellowship from the Cancer Research Institute, New York. This work is supported by the National Cancer Institute of Canada and the Canadian Breast Cancer Research Initiative.

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Authors and Affiliations

  1. Department of Medical Biophysics, University of Toronto and Ontario Cancer Institute, 610 University Avenue, Toronto, M5G 2M9, Ontario, Canada

    Stéphanie A. Backman & Tak W. Mak

  2. Amgen Research Institute, 620 University Avenue, Suite 706, Toronto, M5G 2C1, Ontario, Canada

    Vuk Stambolic, Jillian Haight, Andrew Elia & Tak W. Mak

  3. Department of Molecular Cell Biology, Research Institute for Microbial Diseases, Osaka University, Yamadaoka 3-1, Suita, 565-0874, Osaka, Japan

    Akira Suzuki

  4. Department of Pathology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, 91320-1799, California, USA

    James Pretorius & Brad Bolon

  5. Department of Laboratory Medicine and Pathobiology, University Health Network and University of Toronto, 610 University Avenue, Toronto, M5G 2M9, Ontario, Canada

    Ming-Sound Tsao

  6. Division of Neuropathology, The Toronto Western Hospital and the University Health Care Network, 399 Bathurst St., Toronto, M5T 2S8, Ontario, Canada

    Patrick Shannon

  7. Department of Psychology, University of Toronto, Scarborough Campus, 1265 Military Trail, Scarborough, M1C 1A4, Ontario, Canada

    Gwen O. Ivy

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Correspondence to Tak W. Mak.

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Backman, S., Stambolic, V., Suzuki, A. et al. Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease. Nat Genet 29, 396–403 (2001). https://doi.org/10.1038/ng782

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