Roles of p53 and p27 Kip1 in the regulation of neurogenesis in the murine adult subventricular zone

Abstract

The tumor suppressor protein p53 (Trp53) and the cell cycle inhibitor p27 Kip1 (Cdknb1) have both been implicated in regulating proliferation of adult subventricular zone (aSVZ) cells. We previously reported that genetic ablation of Trp53 (Trp53 −/−) or Cdknb1 (p27 Kip1−/−) increased proliferation of cells in the aSVZ, but differentially affected the number of adult born neuroblasts. We therefore hypothesized that these molecules might play non-redundant roles. To test this hypothesis we generated mice lacking both genes (Trp53 −/−;p27 Kip1−/−) and analysed the consequences on aSVZ cells and adult neuroblasts. Proliferation and self-renewal of cultured aSVZ cells were increased in the double mutants compared with control, but the mice did not develop spontaneous brain tumors. In contrast, the number of adult-born neuroblasts in the double mutants was similar to wild-type animals and suggested a complementation of the p27 Kip1−/− phenotype due to loss of Trp53. Cellular differences detected in the aSVZ correlated with cellular changes in the olfactory bulb and behavioral data on novel odor recognition. The exploration time for new odors was reduced in p27 Kip1−/− mice, increased in Trp53 −/− mice and normalized in the double Trp53−/−;p27 Kip1−/− mutants. At the molecular level, Trp53 −/− aSVZ cells were characterized by higher levels of NeuroD and Math3 and by the ability to generate neurons more readily. In contrast, p27 Kip1−/− cells generated fewer neurons, due to enhanced proteasomal degradation of pro-neural transcription factors. Together, these results suggest that p27 Kip1 and p53 function non-redundantly to modulate proliferation and self-renewal of aSVZ cells and antagonistically in regulating adult neurogenesis.

AMP-activated Protein Kinase Is Involved in Neural Stem Cell Growth Suppression and Cell Cycle Arrest by 5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside and Glucose Deprivation by Down-regulating Phospho-retinoblastoma Protein and Cyclin D

“…Indeed, we measured the level of p53 and p21 proteins after AICAR treatment, but unfortunately, very weak bands were detected in both C17.2 and primary NSCs, consistent with a previous report that p21 and p27 are not enriched in NSCs (31). It was also reported that under physiological conditions, the level of p53 detected in the subventricular zone was very low (49). All of these conclusions are consistent with the rapid proliferation and self-renewal properties of NSCs.…”

CHD7 Maintains Neural Stem Cell Quiescence and Prevents Premature Stem Cell Depletion in the Adult Hippocampus

“…By contrast, the expression of the cell cycle inhibitor, Btg1 , was not affected by the loss of Chd7 (Fig. G) . We also observed a significant increase in the expression of Mtor , a key regulator of adult NSC quiescence and proliferation , in the Chd7null DG (Fig.…”

Chromatin Remodeling Factor Brg1 Supports the Early Maintenance and Late Responsiveness of Nestin-Lineage Adult Neural Stem and Progenitor Cells

“…The link between Brg1 and p53/p21 in regulating stem cells is plausible, as loss of p21 reduces the quiescence and accelerates the exhaustion of aNSC proliferative capacity . Moreover, loss of p53 in aNSCs leads to increased proliferation and dramatically reduced levels of p21 , while increased p53 activity reduces proliferation . Since our results show that Brg1 deletion increases p53 protein and p21 expression in neurospheres, we speculate that iBrg1 stem cells in vivo have increased cell quiescence.…”