title: Neurogenic subventricular zone stem/progenitor cells are Notch1-dependent in their active but not quiescent state.
abstract: The adult mammalian forebrain contains neural stem/progenitor cells (NSCs) that generate neurons throughout life. As in other somatic stem cell systems, NSCs are proposed to be predominantly quiescent and proliferate only sporadically to produce more committed progeny. However, quiescence has recently been shown not to be an essential criterion for stem cells. It is not known whether NSCs show differences in molecular dependence based on their proliferation state. The subventricular zone (SVZ) of the adult mouse brain has a remarkable capacity for repair by activation of NSCs. The molecular interplay controlling adult NSCs during neurogenesis or regeneration is not clear but resolving these interactions is critical in order to understand brain homeostasis and repair. Using conditional genetics and fate mapping, we show that Notch signaling is essential for neurogenesis in the SVZ. By mosaic analysis, we uncovered a surprising difference in Notch dependence between active neurogenic and regenerative NSCs. While both active and regenerative NSCs depend upon canonical Notch signaling, Notch1-deletion results in a selective loss of active NSCs (aNSCs). In sharp contrast, quiescent NSCs (qNSCs) remain after Notch1 ablation until induced during regeneration or aging, whereupon they become Notch1-dependent and fail to fully reinstate neurogenesis. Our results suggest that Notch1 is a key component of the adult SVZ niche, promoting maintenance of aNSCs, and that this function is compensated in qNSCs. Therefore, we confirm the importance of Notch signaling for maintaining NSCs and neurogenesis in the adult SVZ and reveal that NSCs display a selective reliance on Notch1 that may be dictated by mitotic state.
authors.affiliation: Department of Molecular Embryology, Max Planck Institute of Immunobiology and Epigenetics, D-79108 Freiburg, Germany.
authors.forename: Onur
authors.initials: O
authors.lastname: Basak
authors.forename: Claudio
authors.initials: C
authors.lastname: Giachino
authors.forename: Emma
authors.initials: E
authors.lastname: Fiorini
authors.forename: H Robson
authors.initials: HR
authors.lastname: Macdonald
authors.forename: Verdon
authors.initials: V
authors.lastname: Taylor
mesh_terms: D053687:Adult Stem Cells / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D003561:Cytarabine / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007381:Intermediate Filament Proteins / Q000235:genetics; D020547:Lateral Ventricles / Q000166:cytology* / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D022661:RNA, Untranslated; D051881:Receptor, Notch1 / Q000172:deficiency / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics; D055153:Stem Cell Niche / Q000235:genetics / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology; D013997:Time Factors
chemical_list: D002352:Carrier Proteins; D004965:Estrogen Antagonists; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D007166:Immunosuppressive Agents; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; C497762:Notch1 protein, mouse; D018809:Proliferating Cell Nuclear Antigen; D011506:Proteins; D022661:RNA, Untranslated; C497571:Rbpj protein, mouse; D051881:Receptor, Notch1; D011960:Receptors, Estrogen; C010140:estrophilin; D003561:Cytarabine; D013629:Tamoxifen