Single-Cell Analysis of Regional Differences in Adult V-SVZ Neural Stem Cell Lineages

Abstract

SUMMARY The ventricular-subventricular zone (V-SVZ) harbors adult neural stem cells. V-SVZ neural stem cells exhibit features of astrocytes, have a regional identity, and depending on their location in the lateral or septal wall of the lateral ventricle, generate different types of neuronal and glial progeny. We performed large-scale single-cell RNA sequencing to provide a molecular atlas of cells from the lateral and septal adult V-SVZ of male and female mice. This revealed regional and sex differences among adult V-SVZ cells. We uncovered lineage potency bias at the single-cell level among lateral and septal wall astrocytes toward neurogenesis and oligodendrogenesis, respectively. Finally, we identified transcription factor co-expression modules marking key temporal steps in neurogenic and oligodendrocyte lineage progression. Our data suggest functionally important spatial diversity in neurogenesis and oligodendrogenesis in the adult brain and reveal molecular correlates of adult NSC dormancy and lineage specialization.

Galectin‐3 modulates postnatal subventricular zone gliogenesis

“…There is excellent evidence from the Raineteau group that Wnt signaling, which can influence gliogenesis, is restricted to the dorsal SVZ (Azim, Fischer, et al, ; Azim, Rivera, Raineteau, & Butt, ). As well, the Doetsch group have recently shown with single cell RNAseq that the septal SVZ may be primarily gliogenic (Mizrak et al, ). Therefore, in future work it will be important to determine if Gal‐3 regulates gliogenesis in other SVZ subregions.…”

GemC1 is a critical switch for neural stem cell generation in the postnatal brain

“…Here, we show that constitutive or brain-specific deletion of GemC1 results in the development of severe congenital hydrocephalus in mice. We show that lack of GemC1 expression impedes early commitment of showing the number of genes displaying increased or decreased promoter accessibility from GemC1-knockout cells that overlap signature genes for neural stem cells (data from Zywitza, Misios, Bunatyan, Willnow, & Rajewsky, 2018 (Mizrak et al, 2019). A higher number of Ki67+ and DCX-expressing cells was identified in the medial wall of GemC1 cKO brains, suggesting that neurogenesis is positively regulated in the absence of GemC1.…”

“…The upregulation of NSC characteristics raised the question of whether the absence of GemC1 could positively regulate neurogenesis. Under physiological conditions, adult neurogenesis takes place both in the lateral wall, adjacent to the striatum, and the medial wall, next to the septum, albeit in lower rates (Mizrak et al, ). A higher number of Ki67+ and DCX‐expressing cells was identified in the medial wall of GemC1 cKO brains, suggesting that neurogenesis is positively regulated in the absence of GemC1 .…”

Single-cell profiling and SCOPE-seq reveal the lineage dynamics of adult neurogenesis and NOTUM as a key V-SVZ regulator

“…Neurogenesis persists in two principal regions of the adult mouse brain: the subgranular zone of the dentate gyrus and the V-SVZ located in the walls of the lateral ventricles (Doetsch et al, 1999; Fiorelli et al, 2015; Mirzadeh et al, 2008). The V-SVZ contains both quiescent (qNSCs) and actively dividing NSCs (aNSCs) (Codega et al, 2014; Mich et al, 2014) with intrinsic regional identities defined during embryogenesis (Fuentealba et al, 2015), generating different OB interneuron subtypes or glia depending on their location (Brill et al, 2009; Delgado and Lim, 2015; Kohwi et al, 2005; Lopez-Juarez et al, 2013; Merkle et al, 2014; Merkle et al, 2007; Mizrak et al, 2019; Ortega et al, 2013; Zweifel et al, 2018). V-SVZ qNSCs are specialized astrocytes with radial morphology (reviewed in Kriegstein and Alvarez-Buylla, 2009; Mirzadeh et al, 2008), and once activated divide symmetrically, resulting in their depletion over time (Obernier et al, 2018).…”

“…Highly scalable scRNA-seq technologies (Klein et al, 2015; Macosko et al, 2015; Yuan and Sims, 2016; Zheng et al, 2016) have been applied to address cellular heterogeneity and temporal gene expression changes in various stem cell contexts including the V-SVZ field (Mizrak et al, 2019; Tepe et al, 2018; Zywitza et al, 2018); however these V-SVZ studies lacked genetically-induced fate-mapping reporters and could not link V-SVZ NSCs to their progeny in the olfactory bulb. Importantly, current high-throughput methods are unable to link live cell imaging and scRNA-seq data from the same cell, and cannot measure, for example, morphological features of individual cells.…”