Characterization of the molecular mechanisms by which the RB-E2F pathway regulates adult neurogenesis in the olfactory bulb.

Abstract

Adult neurogenesis is an ongoing developmental process that is persistent in two major sites in the mammalian brain throughout life: the adult subventricular zone (aSVZ) linked to the olfactory bulb (OB) and the subgranular zone in the dentate gyrus of the hippocampus. Adult neural stem cells (aNSCs) are relatively quiescent populations that give rise to distinct neuronal subtypes throughout life, yet, at a very low rate and restricted differentiation potential. The Retinoblastoma protein (Rb) is a key cell cycle protein that controls distinct aspects of neurogenesis during development. We have recently shown that targeted loss of Rb in adult neural stem and progenitor cells (NSPCs) leads to a specific increase in progenitor proliferation in the aSVZ but does not affect aNSCs self-renewal nor neuronal migration or terminal differentiation. These findings were also replicated in culture using neurosphere assays derived from Rb--- versus Rb+-- aSVZ tissues. However, Rb is required for the long-term survival of newborn adult OB neurons. Yet, the molecular mechanisms mediating these Rb functions in the adult brain are still unknown. Previous studies have shown that during brain development: 1) Rb regulates neuronal survival through its interaction with E2F1 and-or E2F3 depending on the cell type, 2) each of p107 and E2F3 mediate neural progenitor responsiveness to growth factors specifically through the direct control of the gene encoding the fibroblast growth factor 2 (FGF2) ligand, 3) p130 primarily maintains neuronal survival and inhibits cell cycle re-entry in mature neurons. Moreover, loss of E2F1 impairs adult neurogenesis while p107 negatively regulates self-renewal of aNSCs found in the SVZ. In this study, we investigated whether FGF2, E2F1 and-or E2F3 could be mediating the control of adult neurogenesis by Rb, typically progenitor proliferation control. We also examined potential compensatory role(s) played by two Rb family members, p107 and p130, during neuronal differentiation and-or survival in the a