Original Research ARTICLE
Btg1 is required to maintain the pool of stem and progenitor cells of the dentate gyrus and subventricular zone
- 1 Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia, Rome, Italy
- 2 Department of Human Sciences, LUMSA University, Rome, Italy
- 3 Institute of Translational Pharmacology, National Research Council, Fondazione EBRI Rita Levi-Montalcini, Rome, Italy
- 4 Mouse Biology Unit, European Molecular Biology Laboratory, Monterotondo, Italy
- 5 Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, Université Lyon1, CNRS UMR 5242, INRA UMR1288, Lyon, France
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.
Keywords: BTG family, differentiation, knock out mice, learning and memory, neural stem cells, neurogenic niches, proliferation
Citation: Farioli-Vecchioli S, Micheli L, Saraulli D, Ceccarelli M, Cannas S, Scardigli R, Leonardi L, Cinà I, Costanzi M, Ciotti MT, Moreira P, Rouault J-P, Cestari V and Tirone F (2012) Btg1 is required to maintain the pool of stem and progenitor cells of the dentate gyrus and subventricular zone. Front. Neurosci. 6:124. doi: 10.3389/fnins.2012.00124
Received: 09 May 2012; Accepted: 03 August 2012;
Published online: 30 August 2012.
Edited by:Jack M. Parent, University of Michigan, USA
Reviewed by:Valerie Coronas, Université de Poitiers, France
Gonzalo Alvarez-Bolado, University of Heidelberg, Germany
Copyright: © 2012 Farioli-Vecchioli, Micheli, Saraulli, Ceccarelli, Cannas, Scardigli, Leonardi, Cinà, Costanzi, Ciotti, Moreira, Rouault, Cestari and Tirone. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
*Correspondence: Felice Tirone, Institute of Cell Biology and Neurobiology, Consiglio Nazionale delle Ricerche, Fondazione S.Lucia, via del Fosso di Fiorano 64, 00143 Rome, Italy. e-mail: firstname.lastname@example.org
†Stefano Farioli-Vecchioli and Laura Micheli and Daniele Saraulli and Manuela Ceccarelli have contributed equally to this work.