Neural stem cell quiescence and stemness are molecularly distinct outputs of the Notch3 signaling cascade in the vertebrate adult brain

Than‐Trong, Emmanuel; Ortica-Gatti, Sara; Mella, Sébastien; Nepal, Chirag; Alunni, Alessandro; Bally‐Cuif, Laure

doi:10.1242/dev.161034

Cited by 76 publications

(94 citation statements)

References 74 publications

(106 reference statements)

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“…However, id1 expression was not affected by inflammation 25 . Additionally, Notch signaling, previously shown to be involved in the control of neurogenesis in the zebrafish 41,42 , did not affect id1 expression, either 25 . Our systematic deletion and mutation analysis of the CRM2 module, as well as pharmacological inhibition of the BMP/Smad signaling pathway strongly suggest that BMP signals are crucial for id1 expression in the adult zebrafish telencephalon during both constitutive and regenerative neurogenesis.…”

Section: Bmp As a Regulator Of Id1 Expression During Constitutive Andmentioning

confidence: 68%

Bone morphogenetic protein signaling regulates Id1 mediated neural stem cell quiescence in the adult zebrafish brain via a phylogenetically conserved enhancer module

Zhang

Ferg

Lübke

et al. 2019

Preprint

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AbstractIn the telencephalon of adult zebrafish, the inhibitor of DNA binding 1 (id1) gene is expressed in radial glial cells (RGCs), behaving as neural stem cells (NSCs), during constitutive and regenerative neurogenesis. Id1 controls the balance between resting and proliferating states of RGCs by promoting quiescence. Here, we identified a phylogenetically conserved cis-regulatory module (CRM) mediating the specific expression of id1 in RGCs. Systematic deletion mapping and mutation of conserved transcription factor binding sites in stable transgenic zebrafish lines reveal that this CRM operates via conserved smad1/5 and 4 binding motifs (SBMs) under both homeostatic and regenerative conditions. Transcriptome analysis of injured and uninjured telencephala as well as pharmacological inhibition experiments identify a crucial role of bone morphogenetic protein (BMP) signaling for the function of the CRM. Our data highlight that BMP signals control id1 expression and thus NSC proliferation during constitutive and induced neurogenesis.

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Section: Bmp As a Regulator Of Id1 Expression During Constitutive Andmentioning

confidence: 68%

Bone morphogenetic protein signaling regulates Id1 mediated neural stem cell quiescence in the adult zebrafish brain via a phylogenetically conserved enhancer module

Zhang

Ferg

Lübke

et al. 2019

Preprint

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“…Moreover, multiple Neural G0 genes are significantly enriched in NSCs and glioma Neural G0 cells which are known to help maintain "stemness". For example, HEY1 and TTYH1 (e.g., Fig S3), are both are key players in Notch signaling pathway in NSCs and help maintain the NSC identity in vivo (Kim et al 2018;Than-Trong et al 2018). PTN and its target PTPRZ1 also may help promote stemness, signaling, and proliferation of neural progenitors and glioma tumor cells (Fujikawa et al 2016;Zhang et al 2016;Fujikawa et al 2017).…”

Section: Discussionmentioning

confidence: 99%

Neural G0: a quiescent-like state found in neuroepithelial-derived cells and glioma

Feldman

Toledo

Arora

et al. 2018

Preprint

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In depth knowledge of the cellular states associated with normal and disease tissue homeostasis is critical for understanding disease etiology and uncovering therapeutic opportunities. Here, we used single cell RNA-seq to survey the cellular states of neuroepithelial-derived cells in cortical and neurogenic regions of developing and adult mammalian brain to compare with 38,474 cells obtained from 59 human gliomas, as well as pluripotent ESCs, endothelial cells, CD45+ immune cells, and non-CNS cancers.This analysis suggests that a significant portion of neuroepithelial-derived stem and progenitor cells and glioma cells that are not in G2/M or S phase exist in two states: G1 or Neural G0, defined by expression of certain neuro-developmental genes. In gliomas, higher overall Neural G0 gene expression is significantly associated with less aggressive gliomas, IDH1 mutation, and extended patient survival, while also anticorrelated with cell cycle gene expression. Knockout of genes associated with the Hippo/Yap and p53 pathways diminished Neural G0 in vitro, resulting in faster G1 transit, down regulation of quiescence-associated markers, and loss of Neural G0 gene expression. Thus, Neural G0 is a dynamic cellular state required for indolent cell cycles in neural-specified stem and progenitors poised for cell division. As a result, Neural G0 occupancy may be an important determinant of glioma tumor progression.

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“…To decipher between these hypotheses, we first analysed the expression of highly conserved molecular players of the RG quiescence/activation cycle. Zebrafish adult RG cells are maintained in quiescence by the specific activation of one Notch receptor ortholog, Notch3 (Alunni et al, 2013;Chapouton et al, 2010;Than-Trong et al, 2018). A comparable function of Notch3mediated signalling has been demonstrated in adult mouse neural stem cells (Ehret et al, 2015;Kawai et al, 2017).…”

Section: Rg Enter Premature Notch-dependent Quiescence In Killifishmentioning

confidence: 85%

Mosaic heterochrony in neural progenitors sustains accelerated brain growth and neurogenesis in the juvenile killifish N. furzeri

Coolen

Labusch

Mannioui

et al. 2019

Preprint

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While developmental mechanisms driving increase in brain size during vertebrate evolution are actively studied, we know less of evolutionary strategies allowing to boost brain growth speed. In zebrafish and other vertebrates studied to date, radial glia (RG) constitute the primary neurogenic progenitor population throughout life (Kriegstein and Alvarez-Buylla, 2009); thus, RG activity is a determining factor of growth speed. Here, we ask whether enhanced RG activity is the mechanism selected to drive explosive growth, in adaptation to an ephemeral habitat. In post-hatching larvae of the turquoise killifish, which display drastic developmental acceleration, we show that the dorsal telencephalon (pallium) grows three times faster than in zebrafish. Rather than resulting from enhanced RG activity, we demonstrate that pallial growth is the product of a second type of progenitors (that we term AP for apical progenitors) that actively sustains neurogenesis and germinal zone self-renewal. Intriguingly, AP appear to retain, at larval stages, features of early embryonic progenitors. In parallel, RG enter premature quiescence and express markers of astroglial function. Together, we propose that mosaic heterochrony within the neural progenitor population may permit rapid pallial growth by safeguarding both continued neurogenesis and astroglial function.

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Neural stem cell quiescence and stemness are molecularly distinct outputs of the Notch3 signaling cascade in the vertebrate adult brain

Cited by 76 publications

References 74 publications

Bone morphogenetic protein signaling regulates Id1 mediated neural stem cell quiescence in the adult zebrafish brain via a phylogenetically conserved enhancer module

Bone morphogenetic protein signaling regulates Id1 mediated neural stem cell quiescence in the adult zebrafish brain via a phylogenetically conserved enhancer module

Neural G0: a quiescent-like state found in neuroepithelial-derived cells and glioma

Mosaic heterochrony in neural progenitors sustains accelerated brain growth and neurogenesis in the juvenile killifish N. furzeri

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