Single-Cell Profiling Shows Murine Forebrain Neural Stem Cells Reacquire a Developmental State when Activated for Adult Neurogenesis

Borrett, Michael J.; Innes, Brendan T.; Jeong, Dayae; Tahmasian, Nareh; Storer, Mekayla; Bader, Gary D.; Kaplan, David R.; Miller, Freda D.

doi:10.1016/j.celrep.2020.108022

Cited by 51 publications

(131 citation statements)

References 71 publications

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“…Since cellular differentiation decisions are made at the level of individual cells, elucidation of the underlying molecular mechanisms requires the use of single cell approaches. It is no surprise therefore that recent innovations in single cell molecular profiling technologies have been embraced rapidly by developmental and stem cell biologists, with complete single cell gene expression maps now available for developing embryos of several model organisms (3-5, reviewed in 6), as well as large-scale datasets covering adult tissue homeostasis (7–9).…”

Section: Introductionmentioning

confidence: 99%

Coordinated Changes in Gene Expression Kinetics Underlie both Mouse and Human Erythroid Maturation

Barile

Imaz-Rosshandler

Inzani

et al. 2020

Preprint

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Single cell technologies are transforming biomedical research, including the recent demonstration that unspliced pre-mRNA present in single cell RNA-Seq permits prediction of future expression states. Here we applied this ‘RNA velocity concept’ to an extended timecourse dataset covering mouse gastrulation and early organogenesis. Intriguingly, RNA velocity correctly identified epiblast cells as the starting point, but several trajectory predictions at later stages were inconsistent with both real time ordering and existing knowledge. The most striking discrepancy concerned red blood cell maturation, with velocity-inferred trajectories opposing the true differentiation path. Investigating the underlying causes revealed a group of genes with a coordinated step-change in transcription, thus violating the assumptions behind current velocity analysis suites, which do not accommodate time-dependent changes in expression dynamics. Using scRNA-Seq analysis of chimeric mouse embryos lacking the major erythroid regulator Gata1, we show that genes with the step-changes in expression dynamics during erythroid differentiation fail to be up-regulated in the mutant cells, thus underscoring the coordination of modulating transcription rate along a differentiation trajectory. In addition to the expected block in erythroid maturation, the Gata1- chimera dataset revealed induction of PU.1 and expansion of megakaryocyte progenitors. Finally, we show that erythropoiesis in human fetal liver is similarly characterized by a coordinated step-change in gene expression. By identifying a limitation of the current velocity framework coupled with in vivo analysis of mutant cells, we reveal a coordinated step-change in gene expression kinetics during erythropoiesis, with likely implications for many other differentiation processes.

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Section: Introductionmentioning

confidence: 99%

Coordinated Changes in Gene Expression Kinetics Underlie both Mouse and Human Erythroid Maturation

Barile

Imaz-Rosshandler

Inzani

et al. 2020

Preprint

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“…In the V-SVZ, primary cilia do not only regulate quiescence in radial glia and adult NSCs (Beckervordersandforth et al 2010; Khatri et al 2014), but they are also key to sensing signals present in the cerebrospinal fluid filling the ventricular cavity (Silva-Vargas et al 2016; Monaco et al 2019). Consistent with this view, recent observations have highlighted that in the V-SVZ, acquisition of quiescence concerns a prolonged time period (Borrett et al 2020) and involves different stages and integration of multiple regulatory signals.…”

Section: Discussionmentioning

confidence: 63%

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

Baur

Abdullah

Mandl

et al. 2020

Preprint

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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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“…NSCs in the V-SVZ correspond to a subpopulation of astrocytes (B cells) derived from radial glia (Doetsch et al, 1999; Laywell et al, 2000; Merkle et al, 2004). B cells not only have astrocytic ultrastructure but also express many astrocytic markers (Borrett et al, 2020; Codega et al, 2014). Therefore, identifying markers that distinguish parenchymal astrocytes from B cells has been a challenge in the field.…”

Section: Resultsmentioning

confidence: 99%

“…For example, Nkx6 . 2 , a transcription factor expressed in the ventral embryonic and postnatal ventricular zone (Merkle et al, 2014; Moreno-Bravo et al, 2010), is enriched in cluster B(14), as are Notum and Lmo1 (Fig 3A, Fig 3-S1C) (Borrett et al, 2020; Mizrak et al, 2020). Similarly, Gsx2 , a marker of dorsal B cells, is a marker of cluster B(5) (Fig 3B, Fig 3-S1C).…”

Section: Resultsmentioning

confidence: 99%

“…From the initial interpretation that adult NSCs are multipotent and able to generate a wide range of neuronal cell types (Morshead et al, 1994; Reynolds and Weiss, 1992; van der Kooy and Weiss, 2000), the field has moved to a model of adult NSCs being highly heterogeneous and specialized for the generation of specific types of neurons, and possibly glia (Chaker et al, 2016; Delgado et al, 2020; Fiorelli et al, 2015; Merkle et al, 2014, 2007; Tsai et al, 2012). Previous single-cell sequencing experiments in the V-SVZ have described the many broad classes of cells that reside in the niche.. For example, transcriptional analyses after cell sorting have identified stages in the B-C-A cell lineage (Borrett et al, 2020; Codega et al, 2014; Dulken et al, 2017; Xie et al, 2020), as well as populations of NSCs that appear to activate after injury (Llorens-Bobadilla et al, 2015). Profiling of the entire niche has highlighted differences between quiescent and activated B cells (Mizrak et al, 2020; Zywitza et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Single-cell analysis of the ventricular-subventricular zone reveals signatures of dorsal and ventral adult neurogenic lineages

Redmond

Cebrián-Silla

Nascimento

et al. 2021

Preprint

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The ventricular-subventricular zone (V-SVZ) is home to the largest neurogenic niche in the adult mouse brain. Previous work has demonstrated that resident stem cells in different locations within the V-SVZ produce different subtypes of new neurons for the olfactory bulb. While great progress has been made in understanding the differences in regional stem cell potential using viral and genetic lineage tracing strategies, the core molecular heterogeneity that underlies these regional differences is largely unknown. Here we present single whole-cell and single nucleus sequencing datasets of microdissected adult mouse V-SVZ, and evidence for the existence of two broad populations of adult neural stem cells. By using spatially resolved microdissections in the single nucleus sequencing dataset as a reference, and mapping marker gene expression in the V-SVZ, we find that these two populations reside in largely non-overlapping domains in either the dorsal or ventral V-SVZ. Furthermore, we identified two subpopulations of newly born neurons that have gene expression consistent with dorsal or ventral origins. Finally, we identify genes expressed by both stem cells and the neurons they generate that specifically mark either the dorsal or ventral adult neurogenic lineage. These datasets, methods and findings will facilitate the study of region-specific regulation of adult neurogenesis.

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Single-Cell Profiling Shows Murine Forebrain Neural Stem Cells Reacquire a Developmental State when Activated for Adult Neurogenesis

Cited by 51 publications

References 71 publications

Coordinated Changes in Gene Expression Kinetics Underlie both Mouse and Human Erythroid Maturation

Coordinated Changes in Gene Expression Kinetics Underlie both Mouse and Human Erythroid Maturation

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

Single-cell analysis of the ventricular-subventricular zone reveals signatures of dorsal and ventral adult neurogenic lineages

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