A novel stem cell type at the basal side of the subventricular zone maintains adult neurogenesis

Abstract

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.

Growth/differentiation factor 15 controls number of ependymal and neural stem cells in the ventricular-subventricular zone

“…Apically dividing progenitors in the developing GE will give rise to ependymal and adult NSCs, which to a great extent derive from a common progenitor undergoing proliferation around mid-development (Ortiz-Alvarez et al, 2019) by a mechanism that involves BMP-mediated control of cell cycle regulators (Omiya et al, 2021). Moreover, both apical NSCs and ependymal cells continue to express Prominin in the postnatal SVZ (Baur et al, 2022; Carrillo-Garcia et al, 2010; Khatri et al, 2014). Therefore, we next investigated whether the increase in the proliferation of apically dividing progenitors also affects the generation of these cell types by examining the effect of the genotype on the number of multiciliated ependymal cells and progenitors displaying only one primary cilium at the apical surface of new-born mice at postnatal day 2 (P2).…”

“…The generation of ependymal cells and NSCs is linked as they share a common progenitor (Ortiz-Alvarez et al, 2019). Our analysis focuses here on the effect of GDF15 on apical NSCs, which we have recently shown represent a minor pool of NSCs in the adult V/SVZ are characterized by Prominin-1 expression and display an apical membrane and a primary cilium (Baur et al, 2022). Since basal NSCs likely derive from apical NSCs (Obernier et al, 2018), it is possible that also the number of the latter will be increased in the absence of GDF15, however this issue remains to be investigated.…”

A disintegrin and metalloproteinase 10 (ADAM10) is essential for oligodendrocyte precursor development and myelination in the mouse brain

“…38 In the developing CNS, the function of Notch signaling routinely acts as "lateral inhibition". 39 For example, when Notch-1 binds to its ligand Jagged1, it regulates oligodendrocyte differentiation and myelin formation by promoting OPC proliferation and restricting their maturation. 40 However, it is not unclear whether ADAM10 in OPCs regulates myelination through the Notch1 signalling in the developmental and adult mouse brain.…”

A Disintegrin and Metalloproteinase 10 (ADAM10) Is Essential for Oligodendrocyte Precursor Development and Myelination in the Mouse Brain

“…When a ligand-bearing cell binds to the Notch receptor, it induces a global conformational shift that unfolds the NRR structure to expose S2 cleavage ADAM’s site, [ 36 ] followed by γ-secretase cleavage to release the Notch-intracellular domain (NICD), which translocates to the nucleus and initiates transcription of Notch target genes with binding partners [ 37 ]. In the developing CNS, the function of Notch signaling routinely acts as “lateral inhibition” [ 38 ]. For example, when Notch-1 binds to its ligand Jagged1, it regulates oligodendrocyte differentiation and myelin formation by promoting OPC proliferation and restricting their maturation [ 39 ].…”