Study of the combined roles of the RB family of pocket proteins during adult neurogenesis in the olfactory bulb

Abstract

Adult neurogenesis (AN) is a restricted and highly coordinated process that produces adult-born neurons from a preserved pool of adult neural stem cells (aNSCs). These cells are located in the adult subventricular zone (aSVZ) lining the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus inside the hippocampus. Cell-cycle proteins were shown to be critically involved in brain development, particularly the regulation of embryonic neurogenesis. One such family is the Retinoblastoma (Rb) family of pocket proteins that is comprised of Rb, p107 and p130. We have recently shown that Rb specifically controls neural progenitor cells’ (NPCs) proliferation in the aSVZ without affecting stem cell fate, and is needed for long-term survival of newborn neurons inside the OB and the dentate gyrus. In contrast, p107 was previously shown to negatively regulate adult NSCs self-renewal and promote progenitor commitment to a neuronal fate. Moreover, p130 is required to maintain a post-mitotic state and survival in mature cortical neurons in culture; however, its role in the adult brain is still unknown. Hence, pocket proteins clearly play distinct functions during neurogenesis; yet, they could also carry redundant functions manifested by compensatory mechanisms that are not revealed by studies in single knock-out (KO) models. Here, we show indeed that, compared with single-KOs, loss of all three pocket proteins (triple KO) in aNSPCs leads to additive effects with respect to enhanced stem cell self-renewal and progenitor proliferation but also to unique consequences associated with ectopic neuroblast migration as well as severe and pre-mature loss of immature neurons inside the aSVZ and RMS, prior to reaching the OB. Analysis of double KO mice, confirmed the distinct roles played by p107 and Rb in the control of stem cell self-renewal and progenitor proliferation, respectively. Moreover, it highlighted the central role played by Rb in neuronal survival given that one functional Rb allele is able to rescue th