Loss ofp53Induces Changes in the Behavior of Subventricular Zone Cells: Implication for the Genesis of Glial Tumors

Abstract

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 studyaddressesthesequestionsinmicecarryingthedeletionofp53,atumor-suppressorgeneexpressedintheSVZ.Weshowherethat,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.

p53 Regulates Neural Stem Cell Proliferation and Differentiation via BMP-Smad1 Signaling and Id1

“…2C and 2D). These results, taken together, indicate that p53 -/ -NSCs differentiated into neurons at the sacrifice of astrocytes, supporting the conclusion drawn by Armesilla-Diaz et al that p53 plays a negative role in NSC neural differentiation but a positive role in gliogenesis [26,28,30], but are inconsistent with 2 reports showing that p53 deficiency did not alter neural or glia differentiation of NSCs [23,27]. This discrepancy is not less likely to be caused by genetic backgrounds, as similar results were obtained from NSCs isolated from p53 -/ -mice on 129 and C57BL/6 background ( Supplementary Fig.…”

“…An active role for p53 in NSC proliferation and cell fate determination A role for p53 in NSC differentiation is still debatable as some studies showed that p53 inhibits neural differentiation, whereas the others did not find such a role [26][27][28]. To further clarify this issue, we isolated NSCs from brains of day 13.5 p53…”

“…-/ -and WT embryos (C57BL/6 genetic background) of the same litter with a standard protocol [23,26,28,30]. NSCs from individual embryos formed spheres and were further expanded in proliferation medium containing bFGFs and EGFs.…”

“…However, it is still uncertain how p53 regulates neural differentiation as conflicting results have been reported (reviewed in [18,24,25]). While several studies show that p53 inhibits neuronal lineage, there are studies showing that p53 plays no effect on neuronal differentiation [23,[26][27][28][29][30].…”

Epigenetic setting and reprogramming for neural cell fate determination and differentiation

“…These modifications directly affect the transcriptional activity of p53 and regulate its affinity for diverse cofactors, which in turn regulate the occupancy of p53 in specific promoters [81]. In adult NSCs in the SVZ of p53-deficient mice, loss of p53 was not sufficient for tumour formation, but led to increased cell proliferation and altered differentiation under physiological conditions [82]. p53 was not essential to promote cell death in any of these studies, which also supports the idea that p53 is required to maintain the physiological proliferation rate in NSCs.…”