Quiescence of Adult Mammalian Neural Stem Cells: A Highly Regulated Rest

Urbán, Noelia; Blomfield, Isabelle Maria; Guillemot, François

doi:10.1016/j.neuron.2019.09.026

Cited by 263 publications

(244 citation statements)

References 144 publications

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“…Using RNA-seq expression datasets generated from in vitro and in vivo NSCs, we dissected the relationship between alterations in chromatin accessibility and transcriptional overhaul in NSC activation. The in vitro quiescence system utilized in this study has been shown to be a reliable tool to study the transcriptional profiles of in vivo NSCs 24, 57, 62 . Despite some differences between the datasets, we found strong correlations between chromatin accessibility and gene expression changes in vivo and in vitro.…”

Section: Discussionmentioning

confidence: 99%

Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation

Maybury-Lewis

Brown

Yeary

et al. 2020

Preprint

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20Adult neural stem cells are largely quiescent, and require transcriptional reprogramming 21 to reenter the cell cycle and undergo neurogenesis. However, the precise mechanisms 22 that underlie the rapid transcriptional overhaul during NSC activation remain undefined. 23Here, we identify the genome-wide chromatin accessibility differences between primary 24 neural stem and progenitor cells in quiescent and activated states. We show that these 25 distinct cellular states exhibit both shared and unique chromatin profiles, which are both 26 associated with gene regulation. Interestingly, we find that accessible chromatin states 27 specific to quiescent or activated cells are active enhancers bound by pro-neurogenic 28 and quiescence factors, ASCL1 and NFI. In contrast, shared sites are gene promoters 29 harboring constitutively accessible chromatin enriched for particular core promoter 30 elements that are functionally associated with translation and metabolic functions. 31Together, our findings reveal how accessible chromatin states regulate a transcriptional 32 overhaul and drive the switch between quiescence and proliferation in NSC activation. 33 34 46In vivo, the majority of NSCs reside in a state of quiescence 10 . Quiescent NSCs (qNSCs) 47 have exited the cell cycle but can be prompted by intrinsic or extrinsic cues to "activate" 48 and re-enter the cell cycle (we refer to these cells as activated NSCs, or aNSCs). Once 49 activated, aNSCs proliferate and may return to quiescence and self-renew, or 50 differentiate into neurons or glia. Activation of qNSCs is the first critical step in 51 neurogenesis in the adult brain, and is enhanced in response to damage (e.g. stroke) or 52 environmental stimuli such as parabiosis [11][12][13] . Evidence shows that decreased 53 neurogenesis with age occurs due to reduced activation of qNSCs, senescence of the 54 NSC niche, and exhaustion of the qNSC pool [14][15][16][17] . Accumulation of qNSCs has also been 55 observed in a rodent model for neurodevelopmental disorders, suggesting that a careful 56 balance of NSC quiescence and activation is necessary for healthy cognitive function 18 . 57However, the precise mechanisms that regulate this balance and prompt qNSCs to re-58 enter the cell cycle in the healthy mammalian brain are mostly unknown. 59 60 Recent studies reported that quiescent and activated NSCs employ cell type-specific 61 mechanisms to support their functionality, including distinct metabolic states and 62 differences in proteostasis [19][20][21] . Transcriptional profiling of qNSCs and aNSCs revealed 63 both shared and distinct transcriptional signatures in the two cell types, indicating that a 64 transcriptional overhaul occurs at a subset of genes during the process of NSC 65 activation 10,19,22,23 . For example, genes involved in cell proliferation, lipid metabolism, and 66 protein homeostasis were differentially expressed in quiescent and activated NSCs. 67 Similar changes have also been observed using in vitro models of NSC quiescence and 68 activation...

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Section: Discussionmentioning

confidence: 99%

Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation

Maybury-Lewis

Brown

Yeary

et al. 2020

Preprint

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“…Indirect evidence that NOTCH signaling could have tumor suppressor activity in glioma comes from studies on the proneural transcription factor ASCL1, whose expression is normally repressed by canonical NOTCH targets of the HES/HEY family in NSCs and GSCs [ 78 , 107 , 124 , 142 ]. Lineage tracing experiments in mice have shown that ASCL1 + neural progenitors can be cells of origin of GBM [ 59 , 91 ] and upregulation of ASCL1 and inhibition of NOTCH signaling characterize astrocytoma progression [ 143 ].…”

Section: Notch As a Tumor Suppressor In Gliomamentioning

confidence: 99%

Oncogenic and Tumor-Suppressive Functions of NOTCH Signaling in Glioma

Parmigiani

Taylor

Giachino

2020

Cells

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Although the role of NOTCH signaling has been extensively studied in health and disease, many questions still remain unresolved. Being crucial for tissue homeostasis, NOTCH signaling is also implicated in multiple cancers by either promoting or suppressing tumor development. In this review we illustrate the context-dependent role of NOTCH signaling during tumorigenesis with a particular focus on gliomas, the most frequent and aggressive brain tumors in adults. For a long time, NOTCH has been considered an oncogene in glioma mainly by virtue of its neural stem cell-promoting activity. However, the recent identification of NOTCH-inactivating mutations in some glioma patients has challenged this notion, prompting a re-examination of the function of NOTCH in brain tumor subtypes. We discuss recent findings that might help to reconcile the controversial role of NOTCH signaling in this disease, and pose outstanding questions that still remain to be addressed.

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“…Neural stem cells are mainly quiescent in both neurogenic niches (Urbán et al, 2019). In the SGZ, adult neurogenesis involves the activation of stem cells with radial glia-like morphology, labeled by GFAP, Sox2, nestin, and named type-1 cells, as proposed by Kempermann et al (2004) (Komitova and Eriksson, 2004;Steiner et al, 2006).…”

Section: Adult Neurogenesis In the Dentate Gyrus And Subventricular Zmentioning

confidence: 99%

Interaction Between Neurogenic Stimuli and the Gene Network Controlling the Activation of Stem Cells of the Adult Neurogenic Niches, in Physiological and Pathological Conditions

Ceccarelli

D’Andrea

Micheli

et al. 2020

Front. Cell Dev. Biol.

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Quiescence of Adult Mammalian Neural Stem Cells: A Highly Regulated Rest

Cited by 263 publications

References 144 publications

Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation

Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation

Oncogenic and Tumor-Suppressive Functions of NOTCH Signaling in Glioma

Interaction Between Neurogenic Stimuli and the Gene Network Controlling the Activation of Stem Cells of the Adult Neurogenic Niches, in Physiological and Pathological Conditions

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