Btg1 is Required to Maintain the Pool of Stem and Progenitor Cells of the Dentate Gyrus and Subventricular Zone

Abstract

Btg1 belongs to a family of cell cycle inhibitory genes. We observed that Btg1 is highly expressed in adult neurogenic niches, i.e., the dentate gyrus and subventricular zone (SVZ). Thus, we generated Btg1 knockout mice to analyze the role of Btg1 in the process of generation of adult new neurons. Ablation of Btg1 causes a transient increase of the proliferating dentate gyrus stem and progenitor cells at post-natal day 7; however, at 2 months of age the number of these proliferating cells, as well as of mature neurons, greatly decreases compared to wild-type controls. Remarkably, adult dentate gyrus stem and progenitor cells of Btg1-null mice exit the cell cycle after completing the S phase, express p53 and p21 at high levels and undergo apoptosis within 5 days. In the SVZ of adult (two-month-old) Btg1-null mice we observed an equivalent decrease, associated to apoptosis, of stem cells, neuroblasts, and neurons; furthermore, neurospheres derived from SVZ stem cells showed an age-dependent decrease of the self-renewal and expansion capacity. We conclude that ablation of Btg1 reduces the pool of dividing adult stem and progenitor cells in the dentate gyrus and SVZ by decreasing their proliferative capacity and inducing apoptosis, probably reflecting impairment of the control of the cell cycle transition from G1 to S phase. As a result, the ability of Btg1-null mice to discriminate among overlapping contextual memories was affected. Btg1 appears, therefore, to be required for maintaining adult stem and progenitor cells quiescence and self-renewal.

Genetic control of adult neurogenesis: interplay of differentiation, proliferation and survival modulates new neurons function, and memory circuits

“…Btg1, 65% homologous to PC3/Tis21, is also required for the control of the proliferation of progenitor cells in the dentate gyrus and SVZ, given that its ablation triggers in vivo a strong increase in the number of cycling progenitor cells early after birth (at P7), similar to that observed for PC3/Tis21 (Farioli-Vecchioli et al, 2012b). However, this early postnatal enhancement of proliferation is transient, since in the adult dentate gyrus and SVZ the pool of Btg1-null proliferating stem and progenitor cells strongly decreases, with a higher frequency of exit from the cell cycle followed within a few days by apoptosis (Farioli-Vecchioli et al, 2012b).…”

“…Interestingly, ablation of PC3/Tis21 in the cerebellum causes a significant impairment of migration and differentiation of cerebellar precursors, but does not affect their proliferation; this further suggests that the anti-proliferative and pro-differentiative actions of PC3/Tis21 are dissociable, and also indicates that its anti-proliferative action in cerebellum may be vicariated by other related genes (Farioli-Vecchioli et al, 2012b). …”

Terminal Differentiation of Adult Hippocampal Progenitor Cells Is a Step Functionally Dissociable from Proliferation and Is Controlled by Tis21, Id3 and NeuroD2

“…To obtain the total estimated number of cells within the dentate gyrus, positive for each of the indicated markers, the average number of positive cells per section was multiplied by the total number of 40-μm sections comprising the entire dentate gyrus (about 50–60 sections), as described (Gould et al, 1999; Jessberger et al, 2005; Kee et al, 2007; Farioli-Vecchioli et al, 2008, 2012). Thus, about seven sections per mouse and at least three animals per group were analyzed.…”

Impact of N-tau on adult hippocampal neurogenesis, anxiety, and memory

“…Independent groups of TgN-tau ON (n ¼ 10) and TgN-tau OFF (n ¼ 12) mice were tested in a second water maze protocol, which addresses rodents' ability to perform 1-trial learning and episodiclike memory (Chen et al, 2000;Farioli-Vecchioli et al, 2012;Zeng et al, 2001). In this delayed matching-to-place version of the task, mice are confronted with a series of successive platform locations and trained to navigate to each of them until reaching a rigorous performance criterion (or a maximal number of trials), after which the platform is moved to a different location in the pool and a new training session starts.…”