Abstract 3304: Conditional Pten loss in Olig2 expressing neural stem/progenitor cells results in massive myelination and disruption of the neuronal differentiation in the absence of neoplasia
Authors: Maire Cecile L. , Ramkissoon Shakti H. , Ligon Keith L. 
Published: June 2012

PTEN represents one of the most frequently lost tumor suppressor genes in human cancers with inactivation (deletion or mutation) being particularly frequent in glioblastoma, endometrial cancer, and prostate cancer. Recent work has shown that the functional consequences of Pten loss leading to PI3K pathway activation are highly dependent on cell lineages in which pathway activation occurs. The bHLH transcription factor Olig2 is a critical regulator of stem/progenitor cells in the oligodendroglial lineage and gliomas. In addition, cells of this lineage are likely cells of origin for human GBM. Given these findings, we hypothesized that Pten loss in this lineage might lead to novel insights into stem cell development and glioma formation. To create mice with Pten loss in Olig2+ cells at all stages of development we crossed Olig2-tva-cre (aka Olig2-cre) mice to mice containing a conditional Pten allele. Olig2-Cre:PtenloxP/loxP mice were viable, able to reproduce and grossly normal until 10 months of age when they developed progressive ataxia and hind leg paralysis leading to death. Pathologic exam showed no evidence of CNS tumor or gross developmental abnormalities but instead revealed massively expanded white matter tracts throughout all regions of the CNS associated with severe neurodegenerative changes, inflammation and axonal degeneration. Most interestingly PTEN deletion in the Olig2+ cells revealed an unexpected requirement of Pten in stem cells maintenance and neuronal differentiation. In vitro assay highlighted the increased proliferation and self-renewal capacity of adult and embryonic Olig2-Cre:PtenloxP/loxP neurospheres. Moreover, when cultured with either serum or growth factor, Pten deleted neurospheres harbor a higher number of differentiated inhibitory class neurons leading to more doublecortin positive neuroblasts in the SVZ/RMS as well as post-mitotic calretinin positive neurons in the SVZ and corpus callosum. To explain this phenotype we postulate that either Pten deleted neural stem cells underwent abnormal neuronal differentiation during development leading to excessive production of neurons or that extra neuroblasts born during development that failed to undergo apoptosis due to their Pten deletion. Overall these findings demonstrate that alterations of PTEN/PI3K signaling have unique and dramatic cell type specific effects on oligodendrocytes and neural stem cell within the Olig2 lineage. These findings are of particular importance given the development of PI3K pathway inhibitors destined for use in glioma clinical trials and suggest potential for effects on myelination within treated patients. Further studies will also address the secondary events necessary to promote tumorigenesis by using the Olig2-Cre:PtenloxP/loxP mice as a platform.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3304. doi:10.1158/1538-7445.AM2011-3304