The retinoblastoma protein, pRb, controls adult neurogenesis and the generation of newborn GABAergic neurons in the olfactory bulb -

Abstract

Nerve regeneration in the adult mammalian brain has gained widespread acceptance in the past two decades after the discovery of adult neural stem cells. Several studies have been carried out to uncover the molecular regulation and the functional significance of adult neurogenesis. Despite the fundamental roles played by cell cycle proteins particularly the Retinoblastoma protein, pRb in the control of embryonic neurogenesis, the role of these key cell cycle regulators is still unknown in the adult brain. pRb is a tumor suppressor gene that controls directly neuroblast proliferation and terminal differentiation in the developing brain, and, Rb conditional knockout mice in the telencephalon die at birth. In this study, we have investigated Rb’s role during adult neurogenesis by inducing a temporal Rb deletion specifically in adult neural stem cells and progenitors using Nestin-CreERT2; YFP-YFP mice and Rb floxed-floxed mice. Hence, we deleted Rb in 5-6 weeks old animals and assessed neurogenesis in the olfactory bulb 28 days and 60 days later. As a result, we found a significant increase (1.5-2 folds) in progenitor proliferation in the adult subventricular zone and neuroblast migration along the rostral migratory stream (RMS) in Rb mutant mice compared with littermate controls. Strikingly, we did not detect any defect in terminal differentiation of neuroblasts which exited properly the cell cycle and, subsequently, gave rise to distinct subtypes of GABAergic neurons with respect to their spatio-temporal origin in the OB. However, we observed a proportional increase (1.5-2.5 folds) in newborn OB interneurons expressing Calretinin (CR) and Tyrosine Hydroxylase (TH), two subtypes that are continuously generated throughout life. Our results demonstrate that Rb’s loss leads to enhanced neurogenesis in the OB without affecting the maturation of adult-born interneurons and thus, identify for the first time a requirement for pRb in the control of neuronal regeneration in the adult brain. The findings of this s