Notch1 is required for maintenance of the reservoir of adult hippocampal stem cells

Jessica L. Ables, Nathan A. DeCarolis, Madeleine A. Johnson, Phillip D. Rivera, Zhengliang Gao, Don C. Cooper, Freddy Radtke, Jenny Hsieh, Amelia J Eisch

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187 Scopus citations

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/Notch1loxP/loxP [Notch1 inducible 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/Notch1w/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.

Original languageEnglish (US)
Pages (from-to)10484-10492
Number of pages9
JournalJournal of Neuroscience
Volume30
Issue number31
DOIs
StatePublished - Aug 4 2010

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ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Ables, J. L., DeCarolis, N. A., Johnson, M. A., Rivera, P. D., Gao, Z., Cooper, D. C., Radtke, F., Hsieh, J., & Eisch, A. J. (2010). Notch1 is required for maintenance of the reservoir of adult hippocampal stem cells. Journal of Neuroscience, 30(31), 10484-10492. https://doi.org/10.1523/JNEUROSCI.4721-09.2010