NDLI: Differential transformation capacity of neuro-glial progenitors during development

Content Provider	PubMed Central
Author	Muñoz, Diana Marcela Singh, Sanjay Tung, Takyee Agnihotri, Sameer Nagy, Andras Guha, Abhijit Zadeh, Gelareh Hawkins, Cynthia
Abstract	Gliomas represent the most common type of brain tumor, but show considerable variability in histologic appearance and clinical outcome. The phenotypic differences between types and grades of gliomas have not been explained solely on the grounds of differing oncogenic stimuli. Several studies have demonstrated that some phenotypic differences may be attributed to regional differences in the neural stem cells from which tumors arise. We hypothesized that temporal differences may also play a role, with tumor phenotypic variability reflecting intrinsic differences in neural stem cells at distinct developmental stages. To determine how the tumorigenic potential of lineally related stem cells changes over time, we used a conditional transgenic system that integrates Cre-Lox–mediated and Tet-regulated expression to drive K-rasG12D expression in neuro-glial progenitor populations at different developmental time points. Using this model, we demonstrate that K-rasG12D–induced transformation is dependent on the developmental stage at which it is introduced. Diffuse malignant brain tumors develop during early embryogenesis but not when K-rasG12D expression is induced during late embryogenesis or early postnatal life. We show that differential expression of cell-cycle regulators during development may be responsible for this differing susceptibility to malignant transformation and that loss of p53 can overcome the transformation resistance seen at later developmental stages. These results highlight the interplay between genetic alterations and the molecular changes that accompany specific developmental stages; early progenitors may lack the regulatory mechanisms present at later, more lineage-restrictive, developmental time points, making them more susceptible to transformation.
Related Links	http://dx.doi.org/10.1073/pnas.1303504110
Ending Page	14383
Page Count	6
Starting Page	14378
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	35
Volume Number	110
Language	English
Publisher	National Academy of Sciences
Publisher Date	2013-08-27
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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