title: Notch1 is required for maintenance of the reservoir of adult hippocampal stem cells.
abstract: Notch1 regulates neural stem cell (NSC) number during development, but its role in adult neurogenesis is unclear. We generated nestin-CreER(T2)/R26R-YFP/Notch1(loxP/loxP) [Notch1inducible knock-out (iKO)] mice to allow tamoxifen (TAM)-inducible elimination of Notch1 and concomitant expression of yellow fluorescent protein (YFP) in nestin-expressing Type-1 NSCs and their progeny in the adult hippocampal subgranular zone (SGZ). Consistent with previous research, YFP+ cells in all stages of neurogenesis were evident in the subgranular zone (SGZ) of wild-type (WT) mice (nestin-CreER(T2)/R26R-YFP/Notch1(w/w)) after tamoxifen (post-TAM), producing adult-generated YFP+ dentate gyrus neurons. Compared with WT littermates, Notch1 iKO mice had similar numbers of total SGZ YFP+ cells 13 and 30 d post-TAM but had significantly fewer SGZ YFP+ cells 60 and 90 d post-TAM. Significantly fewer YFP+ Type-1 NSCs and transiently amplifying progenitors (TAPs) resulted in generation of fewer YFP+ granule neurons in Notch1 iKO mice. Strikingly, 30 d of running rescued this deficit, as the total YFP+ cell number in Notch iKO mice was equivalent to WT levels. This was even more notable given the persistent deficits in the Type-1 NSC and TAP reservoirs. Our data show that Notch1 signaling is required to maintain a reservoir of undifferentiated cells and ensure continuity of adult hippocampal neurogenesis, but that alternative Notch- and Type-1 NSC-independent pathways compensate in response to physical activity. These data shed light on the complex relationship between Type-1 NSCs, adult neurogenesis, the neurogenic niche, and environmental stimuli.
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Ables
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Decarolis
authors.forename: Madeleine A
authors.initials: MA
authors.lastname: Johnson
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Rivera
authors.forename: Zhengliang
authors.initials: Z
authors.lastname: Gao
authors.forename: Don C
authors.initials: DC
authors.lastname: Cooper
authors.forename: Freddy
authors.initials: F
authors.lastname: Radtke
authors.forename: Jenny
authors.initials: J
authors.lastname: Hsieh
authors.forename: Amelia J
authors.initials: AJ
authors.lastname: Eisch
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism*; D000818:Animals; D002452:Cell Count; D006624:Hippocampus / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D010805:Physical Conditioning, Animal / Q000502:physiology; D051881:Receptor, Notch1 / Q000378:metabolism*
chemical_list: D051881:Receptor, Notch1