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

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).

PTEN signaling in brain: neuropathology and tumorigenesis

“…Similarly, the focal lesions in LDD rarely contain proliferative cells, as distinct from malignancies in which the second allele of PTEN has been inactivated by mutation. Further, some dysplastic neurons are ectopically placed in the molecular layer in LDD, similar to ectopically positioned granule neurons resulting from a neuronal migration defect in the mouse model (Backman et al, 2001;Kwon et al, 2001;Abel et al, 2005). Indeed, deletion of Pten in multiple neuronal types during development results in profound defects in migration and patterning in brain (Backman et al, 2001;Groszer et al, 2001;Kwon et al, 2001;Marino et al, 2002;Yue et al, 2005).…”

“…Although patients have inherited one mutant copy of PTEN, the dysplastic cells have either complete loss of PTEN expression or express only the mutant allele, which is accompanied by elevated phosphorylated AKT (Iida et al, 1998;Zhou et al, 2003;Abel et al, 2005). The features of LDD were recapitulated in mouse models where Pten was conditionally deleted late in development of granule neurons of the cerebellum resulting in a cell-autonomous loss of size regulation (Backman et al, 2001;Kwon et al, 2001). In the mouse, the size of Ptendeficient granule neurons progressively increases without evidence of abnormal proliferation.…”

Endothelial cells promote neural stem cell proliferation and differentiation associated with VEGF activated Notch and Pten signaling

“…Notch signaling is thought to maintain ''stemness'' and to prevent exit from the cell cycle and maturation (Basak and Taylor, 2009). However, its role in adult neurogenesis remains unclear, primarily because Notch plays so many other roles in maturation, neuroplasticity, and survival (Carlson and Conboy, 2007;Corbin et al, 2008 (Backman et al, 2001;Kwon et al, 2001;Groszer et al, 2001). Conditional knockout of Pten in neural stem cells revealed that Pten is indispensable for proper control of neural stem cell proliferation and self-renewal in the developing brain (Groszer et al, 2001).…”

Post-translational regulation of PTEN

“…Additionally, PTEN was shown to control ovarian follicle activation and therefore reproduction of mammals (Reddy et al, 2008). The roles of PTEN in the development and function of specific organs/tissues, such as brain, heart, and bone, have also been reported (Backman et al, 2001;Groszer et al, 2001;Kwon et al, 2001Kwon et al, , 2006Crackower et al, 2002;Liu et al, 2007;Oudit et al, 2008).…”

“…The strong evidence for this argument is that many physiological abnormalities and tumorigenesis caused by the loss of PTEN function are associated with Akt activation and can be attenuated by pharmacological inhibition of PI3K, Akt or downstream components such as, mammalian Target of Rapamycin (mTOR) (Backman et al, 2001;Groszer et al, 2001;Kwon et al, 2001Kwon et al, , 2006Crackower et al, 2002;Liu et al, 2007;Oudit et al, 2008).…”