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The Journal of Neuroscience, January 25, 2006, 26(4):1107-1116; doi:10.1523/JNEUROSCI.3970-05.2006

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Neurobiology of Disease
Loss of p53 Induces Changes in the Behavior of Subventricular Zone Cells: Implication for the Genesis of Glial Tumors

Sara Gil-Perotin,^1,2 Mireya Marin-Husstege,¹ Jiadong Li,¹ Mario Soriano-Navarro,^2,3 Frederique Zindy,⁴ Martine F. Roussel,^4 * Jose-Manuel Garcia-Verdugo,^2,3 * and Patricia Casaccia-Bonnefil¹

¹Department Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, ²Department Comparative Neurobiology, Instituto Cavanilles, University of Valencia, 46980 Valencia, Spain, ³Department of Cellular Therapy, Centro de Investigación Príncipe Felipe, Valencia, 46013 Valencia, Spain, and ⁴Department of Tumor Cell Biology and Genetics, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105

Correspondence should be addressed to Patrizia Casaccia-Bonnefil, Department Neuroscience, R-304, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854. Email: casaccpa{at}umdnj.edu

The role of multipotential progenitors and neural stem cells in the adult subventricular zone (SVZ) as cell-of-origin of glioblastoma has been suggested by studies on human tumors and transgenic mice. However, it is still unknown whether glial tumors are generated by all of the heterogeneous SVZ cell types or only by specific subpopulations of cells. It has been proposed that transformation could result from lack of apoptosis and increased self-renewal, but the definition of the properties leading to neoplastic transformation of SVZ cells are still elusive. This study addresses these questions in mice carrying the deletion of p53, a tumor-suppressor gene expressed in the SVZ. We show here that, although loss of p53 by itself is not sufficient for tumor formation, it provides a proliferative advantage to the slow- and fast-proliferating subventricular zone (SVZ) populations associated with their rapid differentiation. This results in areas of increased cell density that are distributed along the walls of the lateral ventricles and often associated with increased p53-independent apoptosis. Transformation occurs when loss of p53 is associated with a mutagenic stimulus and is characterized by dramatic changes in the properties of the quiescent adult SVZ cells, including enhanced self-renewal, recruitment to the fast-proliferating compartment, and impaired differentiation.

Together, these findings provide a cellular mechanism for how the slow-proliferating SVZ cells can give rise to glial tumors in the adult brain.

Key words: differentiation; proliferation; subependymal zone; glia; neurogenesis; cell cycle

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Received Sept. 19, 2005; revised Nov. 18, 2005; accepted Dec. 7, 2005.

Correspondence should be addressed to Patrizia Casaccia-Bonnefil, Department Neuroscience, R-304, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854. Email: casaccpa{at}umdnj.edu

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