Somatic inactivation of PTEN occurs in different human tumors including glioblastoma, endometrial carcinoma and prostate carcinoma. Germline mutations in PTEN result in a range of phenotypic abnormalities that occur with variable penetrance, including neurological features such as macrocephaly, seizures, ataxia and Lhermitte-Duclos disease (also described as dysplastic gangliocytoma of the cerebellum). Homozygous deletion of Pten causes embryonic lethality in mice. To investigate function in the brain, we used Cre-loxP technology to selectively inactivate Pten in specific mouse neuronal populations. Loss of Pten resulted in progressive macrocephaly and seizures. Neurons lacking Pten expressed high levels of phosphorylated Akt and showed a progressive increase in soma size without evidence of abnormal proliferation. Cerebellar abnormalities closely resembled the histopathology of human Lhermitte-Duclos disease. These results indicate that Pten regulates neuronal size in vivo in a cell-autonomous manner and provide new insights into the etiology of Lhermitte-Duclos disease.
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The authors thank T. Curran, P. McKinnon, M. Yuzaki, L.H. Ellenson and C. Wetmore for helpful discussions, L. Li for transgenic microinjections, Y. Lee, D. Rice, J. Wigle, S. Magdaleno, J. Cunningham and S. Lloyd for technical advice, G. Murti and K. Barnes for confocal microscopy and T. Mak and S. Backman for discussing results prior to publication. This work was supported in part by a National Institutes of Health (NIH) Cancer Center Support CORE grant, NIH grants CA21765 and CA71907 (S.J.B.) and the American Lebanese Syrian Associated Charities (ALSAC).
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