title: Mammalian target of rapamycin signaling is a key regulator of the transit-amplifying progenitor pool in the adult and aging forebrain.
abstract: Adult forebrain neurogenesis is dynamically regulated. Multiple families of niche-derived cues have been implicated in this regulation, but the precise roles of key intracellular signaling pathways remain vaguely defined. Here, we show that mammalian target of rapamycin (mTOR) signaling is pivotal in determining proliferation versus quiescence in the adult forebrain neural stem cell (NSC) niche. Within this niche, mTOR complex-1 (mTORC1) activation displays stage specificity, occurring in transiently amplifying (TA) progenitor cells but not in GFAP+ stem cells. Inhibiting mTORC1 depletes the TA progenitor pool in vivo and suppresses epidermal growth factor (EGF)-induced proliferation within neurosphere cultures. Interestingly, mTORC1 inhibition induces a quiescence-like phenotype that is reversible. Likewise, mTORC1 activity and progenitor proliferation decline within the quiescent NSC niche of the aging brain, while EGF administration reactivates the quiescent niche in an mTORC1-dependent manner. These findings establish fundamental links between mTOR signaling, proliferation, and aging-associated quiescence in the adult forebrain NSC niche.
authors.affiliation: Department of Pathology and Cell Biology, Groupe de recherche sur le système nerveux central and Center of Excellence in Neuroscience of the Université de Montréal, Université de Montréal, Montréal, Quebec, Canada, H3T 1J4.
authors.forename: Grigorios N
authors.initials: GN
authors.lastname: Paliouras
authors.forename: Laura K
authors.initials: LK
authors.lastname: Hamilton
authors.forename: Anne
authors.initials: A
authors.lastname: Aumont
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Joppé
authors.forename: Fanie
authors.initials: F
authors.lastname: Barnabé-Heider
authors.forename: Karl J L
authors.initials: KJ
authors.lastname: Fernandes
mesh_terms: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D000375:Aging; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D000089622:Doublecortin Domain Proteins; D004622:Embryo, Mammalian; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D042282:Microdissection; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D011247:Pregnancy; D016548:Prosencephalon / Q000166:cytology*; D038601:Ribosomal Protein S6 / Q000378:metabolism; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D020123:Sirolimus / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014404:Tubulin / Q000378:metabolism
chemical_list: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D051792:Basic Helix-Loop-Helix Proteins; D000089622:Doublecortin Domain Proteins; D016222:Fibroblast Growth Factor 2; D005346:Fibroblast Growth Factors; D005904:Glial Fibrillary Acidic Protein; D049452:Green Fluorescent Proteins; D019394:Ki-67 Antigen; D008869:Microtubule-Associated Proteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D000076104:Oligodendrocyte Transcription Factor 2; D038601:Ribosomal Protein S6; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014404:Tubulin; C499317:Ascl1 protein, mouse; C512773:Olig2 protein, mouse; C462941:beta3 tubulin, mouse; C546843:mTOR protein, mouse