Summary In the adult subependymal zone (SEZ), neural stem cells (NSCs) apically contacting the lateral ventricle on activation generate progenitors proliferating at the niche basal side. We here show that Tailless (TLX) coordinates NSC activation and basal progenitor proliferation by repressing the NOTCH effector Hes1 . Consistent with this, besides quiescence Hes1 expression also increases on Tlx mutation. Since HES1 levels are higher at the apical SEZ, NOTCH activation is increased in Tlx −/− NSCs, but not in surrounding basal progenitors. Underscoring the causative relationship between higher HES1/NOTCH and increased quiescence, downregulation of Hes1 only in mutant NSCs normalizes NOTCH activation and resumes proliferation and neurogenesis not only in NSCs, but especially in basal progenitors. Since pharmacological blockade of NOTCH signaling also promotes proliferation of basal progenitors, we conclude that TLX, by repressing Hes1 expression, counteracts quiescence and NOTCH activation in NSCs, thereby relieving NOTCH-mediated lateral inhibition of proliferation in basal progenitors.
According to the current consensus, murine neural stem cells (NSCs) apically contacting the lateral ventricle generate differentiated progenitors by rare asymmetric divisions or by relocating to the basal side of the ventricular-subventricular zone (V-SVZ). Both processes will ultimately lead to the generation of adult-born olfactory bulb (OB) interneurons. In contrast to this view, we here find that adult-born OB interneurons largely derive from an additional NSC-type resident in the basal V-SVZ. Despite being both capable of self-renewal and long-term quiescence, apical and basal NSCs differ in Nestin expression, primary cilia extension and frequency of cell division. The expression of Notch-related genes also differs between the two NSC groups, and Notch activation is greatest in apical NSCs. Apical downregulation of Notch-effector Hes1 decreases Notch activation while increasing proliferation across the niche and neurogenesis from apical NSCs. Underscoring their different roles in neurogenesis, lactation-dependent increase in neurogenesis is paralleled by extra activation of basal but not apical NSCs. Thus, basal NSCs support OB neurogenesis, whereas apical NSCs impart Notch-mediated lateral inhibition across the V-SVZ.
Neural stem cells (NSCs) in the ventricular-subventricular zone (V-SVZ) contribute to olfaction by being the origin of most adult-born olfactory bulb (OB) interneurons. The current consensus maintains that adult NSCs are radial glialike progenitors apically contacting the lateral ventricle and generating intermediate progenitors migrating at the basal V-SVZ. Whether basal NSCs are present in the V-SVZ is unknown. We here used genetic tagging of NSCs in vivo and additional labelling approaches to reveal that basal NSCs lacking apical attachment represent the largest NSC type in the postnatal V-SVZ from birth onwards. Despite dividing faster than their apical counterpart, basal NSCs still undergo long-term self-renewal and quiescence. Unlike apical NSCs, they are largely devoid of primary cilia and Prominin-1, Nestin and glial fibrillary acidic protein (GFAP) immunoreactivity. Six weeks after viral tagging of apical cells, few descendant cells were detected in the basal V-SVZ, including Sox9+ progenitors and GFAP+ astrocytes, and very rare new neurons in the OB, indicating that adult-born OB neurons originate from basal and not apical NSCs. Consistent with this, we found that pregnancy, a physiological modulator of adult OB neurogenesis, selectively increases the number of basal but not apical NSCs. Lastly, we find that apical NSCs display the highest levels of Notch activation in the neural lineage, and that selective apical downregulation of Notch-signaling effector Hes1 decreases Notch activation while increasing proliferation across the V-SVZ. Thus, apical NSCs act essentially as neurogenesis gatekeepers by modulating Notch-mediated lateral inhibition of proliferation in the adult V-SVZ.Graphical AbstractHighlightsBasal NSCs are the most abundant stem cell type in the adult V-SVZ from birth onwards.Apical and basal NSCs display distinct characteristics and cell cycle progression dynamics.Apical NSCs are not the main source of newly generated adult OB interneurons.Apical NSCs regulate intermediate progenitor proliferation by orchestrating Notch-mediated lateral inhibition.
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