Study Of The Combined Roles Of p53 And Rb in the Maintenance Of A Post-Mitotic State in Adult-Born Neurons Inside the Olfactory Bulb

Abstract

Adult neurogenesis (AN) is an ongoing process in two neurogenic niches inside the adult mammalian brain: the adult subventricular zone (aSVZ) and the sub-granular zone (SGZ) of the dentate gyrus. This process generates a continuous supply of newborn neurons in the olfactory bulb (OB) and the hippocampus, respectively. The population of adult neural stem and progenitor cells (aNSPCs) is limited in size and gradually loses its neurogenic capacity with age. Given the promising regenerative potential associated with AN, it is essential to decipher the key molecular pathways that control it in order to enhance the brain’s regenerative capacity. Retinoblastoma (Rb) and p53 are two key tumor suppressor proteins that regulate the cell cycle as well as cell survival. Our laboratory has shown that Rb negatively controls progenitor cell proliferation in the adult SVZ and is needed for the long-term survival of newborn OB neurons (Naser et al., 2016). We also found that cell death of Rb-/- OB neurons is not rescued by the loss of p53. More recently, we uncovered that Rb protects these neurons against cell cycle re-entry (CCE) and accumulation of DNA damage by maintaining a post-mitotic state (Omais et al., 2022). The role of p53 in the latter context is still unknown. Here, we examined whether p53 either alone or in combination with Rb can protect newborn OB neurons against CCE and DNA damage. Our results show that p53 negatively controls the rate of OB neurogenesis in a dose-dependent manner. However, unlike Rb, loss of p53 does not predispose OB neurons to CCE or DNA damage one month following its deletion. Moreover, the compound deletion of p53 and Rb does not exacerbate the CCE and DDR phenotype reported in the absence of Rb. We also show that Rb-/- newborn neurons in the glomerular layer (GL) but not the granule cell layer (GCL) are resistant to CCE and cell death. Hence, they accumulate DNA damage but are able to progress into the M phase. Altogether, our data indicate that p53 is not required for the maintenance of a post-mitotic state in newborn OB neurons at least in the short term. In addition, the GL and GCL exhibit distinct regulatory dynamics with respect to cell cycle control and neuronal survival. These findings contribute to a better understanding of the molecular pathways involved in the control of AN inside the OB, which affect the regenerative capacity of the adult brain.