title: Physical exercise rescues defective neural stem cells and neurogenesis in the adult subventricular zone of Btg1 knockout mice.
abstract: Adult neurogenesis occurs throughout life in the dentate gyrus (DG) and the subventricular zone (SVZ), where glia-like stem cells generate new neurons. Voluntary running is a powerful neurogenic stimulus triggering the proliferation of progenitor cells in the DG but, apparently, not in the SVZ. The antiproliferative gene Btg1 maintains the quiescence of DG and SVZ stem cells. Its ablation causes intense proliferation of DG and SVZ stem/progenitor cells in young mice, followed, during adulthood, by progressive decrease of the proliferative capacity. We have previously observed that running can rescue the deficit of DG Btg1-null neurogenesis. Here, we show that in adult Btg1-null SVZ stem and neuroblast cells, the reduction of proliferation is associated with a longer cell cycle and a more frequent entry into quiescence. Notably, running increases proliferation in Btg1-null SVZ stem cells highly above the levels of sedentary wild-type mice and restores normal values of cell cycle length and quiescence in stem and neuroblast cells, without affecting wild-type cells. Btg1-null SVZ neuroblasts show also increased migration throughout the rostral migratory stream and a deficiency of differentiated neurons in the olfactory bulb, possibly a consequence of premature exit from the cycle; running, however, normalizes migration and differentiation, increasing newborn neurons recruited to the olfactory circuitry. Furthermore, running increases the self-renewal of Btg1-null SVZ-derived neurospheres and, remarkably, in aged Btg1-null mice almost doubles the proliferating SVZ stem cells. Altogether, this reveals that SVZ stem cells are endowed with a hidden supply of self-renewal capacity, coupled to cell cycle acceleration and emerging after ablation of the quiescence-maintaining Btg1 gene and following exercise.
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia, via del Fosso di Fiorano 64, 00143, Rome, Italy.|Dipartimento di Biologia e Biotecnologie Charles Darwin, Sapienza Università di Roma, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Mastrorilli
authors.affiliation: University Roma 3, Rome, Italy.|European Brain Research Institute (EBRI), Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Scopa
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia, via del Fosso di Fiorano 64, 00143, Rome, Italy.|Department of Human Sciences, LUMSA University, Rome, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Saraulli
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia, via del Fosso di Fiorano 64, 00143, Rome, Italy.|Department of Human Sciences, LUMSA University, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Costanzi
authors.affiliation: European Brain Research Institute (EBRI), Rome, Italy.|Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Scardigli
authors.affiliation: Centre Léon Bérard-Université Claude Bernard Lyon I, Lyon, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Rouault
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia, via del Fosso di Fiorano 64, 00143, Rome, Italy. stefano.fariolivecchioli@cnr.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Farioli-Vecchioli
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia, via del Fosso di Fiorano 64, 00143, Rome, Italy. felice.tirone@cnr.it.
authors.forename: Felice
authors.identifier: http://orcid.org/0000-0002-0980-4377
authors.initials: F
authors.lastname: Tirone
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D016922:Cellular Senescence; D005838:Genotype; D020547:Lateral Ventricles / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000172:deficiency* / Q000235:genetics; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D055495:Neurogenesis; D010641:Phenotype; D010805:Physical Conditioning, Animal; D061251:Primary Cell Culture; D012420:Running; D018874:Spheroids, Cellular; D013997:Time Factors; D046509:Tissue Culture Techniques
chemical_list: C489552:Btg1 protein, mouse; D009363:Neoplasm Proteins
keywords: Adult neurogenesis; Cell cycle kinetics; Differentiation; Neural stem/progenitor cells; Proliferation; Running