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Article
Nature Genetics  29, 396 - 403 (2001)
Published online: 19 November 2001; | doi:10.1038/ng782

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

Stéphanie A. Backman1, Vuk Stambolic2, Akira Suzuki3, Jillian Haight2, Andrew Elia2, James Pretorius4, Ming-Sound Tsao5, Patrick Shannon6, Brad Bolon4, Gwen O. Ivy7 & Tak W. Mak1, 2

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

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

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

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

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

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

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

Correspondence should be addressed to Tak W. Mak tmak@oci.utoronto.ca
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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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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