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.

Notch3 signaling gates cell cycle entry and limits neural stem cell amplification in the adult pallium

“…Although the mammalian SEZ/SGZ and the zebrafish medial pallium, analyzed here, are not directly homologous domains (Salas et al, 2006;Mueller et al, 2011), their NSCs share fundamental characteristics, such as quiescence, glial attributes and gene expression (Adolf et al, 2006). The fact that Notch receptors other than Notch1 must control adult NSC proliferation/activation was recently hypothesized in the mouse based on the different phenotypes of invalidating RBPJk compared with Notch1 (Basak et al, 2012). The conditional ablation of RBPJk in adult neural progenitors of the SEZ and SGZ led to a transient increase in proliferation of NSCs (Ehm et al, 2010) and, to a larger extent, of the TAP population (Ehm et al, 2010;Imayoshi et al, 2010).…”

Notch signaling in the brain: In good and bad times

“…It has been shown that ablation of RBPJK in adult neural stem cells (NSCs) of the SVZ induces a transient increase in neurogenesis but leads in the long term to a permanent depletion of the progenitor pool . Another recent study, using conditional deletion mouse models for Notch1 and RBPJK in adult NSC of the SVZ, has confirmed that loss of functional Notch signaling exhausts the progenitor pool (Basak et al, 2012). This same study indicates a functional separation between Notch1 and RBPJK function and indicates that Notch1 does not regulate the cell fate of quiescent NSCs, which, instead, appears to be under RBPJK regulation, probably through the other heterologous receptors, Notch2 and Notch3.…”

“…In the mature brain, Notch signaling is additionally implicated in adult neurogenesis of the subventricular zone (SVZ) (Basak et al, 2012;Imayoshi et al, 2010;Nyfeler et al, 2005) and subgranular zone of the hippocampus (SGZ) (Lugert et al, 2010). Neurogenesis, and integration of new born neurons is thought to contribute to olfaction (SVZ) (Sakamoto et al, 2011) and spatial memory (SGZ) (Kempermann and Gage, 2002).…”

“…Canonical Notch/RBPJK signaling is essential in maintaining a neurogenic pool in the mature brain (Basak et al, 2012;Imayoshi et al, 2010;Lugert et al, 2010). It has been shown that ablation of RBPJK in adult neural stem cells (NSCs) of the SVZ induces a transient increase in neurogenesis but leads in the long term to a permanent depletion of the progenitor pool .…”

“…This same study indicates a functional separation between Notch1 and RBPJK function and indicates that Notch1 does not regulate the cell fate of quiescent NSCs, which, instead, appears to be under RBPJK regulation, probably through the other heterologous receptors, Notch2 and Notch3. The group of Taylor has also demonstrated, at least in two papers, that Notch1 is important in maintaining an actively proliferating NSCs pool, which selectively lost during aging (Basak et al, 2012;Lugert et al, 2010).…”