Forebrain ependymal cells are Notch-dependent and generate neuroblasts and astrocytes after stroke

Carlén, Marie; Meletis, Konstantinos; Göritz, Christian; Darsalia, Vladimer; Evergren, Emma; Tanigaki, Kenji; Amendola, Mario; Barnabé-Heider, Fanie; Yeung, Maggie S. Y.; Naldini, Luigi; Honjo, Tasuku; Kokaia, Zaal; Shupliakov, Oleg; Cassidy, Robert M.; Lindvall, Olle; Frisén, Jonas

doi:10.1038/nn.2268

Cited by 404 publications

(421 citation statements)

References 43 publications

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“…6d). This is in agreement with data from Carlén et al, stating that ependymal cells lining the LV wall receive active Notch1 signals (Carlen et al, 2009).…”

supporting

confidence: 93%

Generation and characterization of a Notch1 signaling‐specific reporter mouse line

Smith

Claudinot

Lehal

et al. 2012

Genesis

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Signaling through the Notch1 receptor is essential for the control of numerous developmental processes during embryonic life as well as in adult tissue homeostasis and disease. Since the outcome of Notch1 signaling is highly context‐dependent, and its precise physiological and pathological role in many organs is unclear, it is of great interest to localize and identify the cells that receive active Notch1 signals in vivo. Here, we report the generation and characterization of a BAC‐transgenic mouse line, N1‐Gal4VP16, that when crossed to a Gal4‐responsive reporter mouse line allowed the identification of cells undergoing active Notch1 signaling in vivo. Analysis of embryonic and adult N1‐Gal4VP16 mice demonstrated that the activation pattern of the transgene coincides with previously observed activation patterns of the endogenous Notch1 receptor. Thus, this novel reporter mouse line provides a unique tool to specifically investigate the spatial and temporal aspects of Notch1 signaling in vivo. genesis 50:700–710, 2012. © 2012 Wiley Periodicals, Inc.

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“…6d). This is in agreement with data from Carlén et al, stating that ependymal cells lining the LV wall receive active Notch1 signals (Carlen et al, 2009).…”

supporting

confidence: 93%

Generation and characterization of a Notch1 signaling‐specific reporter mouse line

Smith

Claudinot

Lehal

et al. 2012

Genesis

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“…Whereas the dentate gyrus generates granule neurons for the local hippocampal circuitry, the subventricular zone (SVZ) produces multiple interneuron types within the olfactory network. The cellular composition of the SVZ has been characterized in detail and specialized astrocytes are NSCs (Doetsch et al, 1999b;Johansson et al, 1999;Morshead et al, 2003;Coskun et al, 2008;Meletis et al, 2008;Carlén et al, 2009). SVZ NSCs are a heterogeneous cell population and their spatial distribution correlates with distinct cellular fates (Kohwi et al, 2007;Merkle et al, 2007;Young et al, 2007a).…”

Section: Introductionmentioning

confidence: 99%

Neurogenic Subventricular Zone Stem/Progenitor Cells Are Notch1-Dependent in Their Active But Not Quiescent State

Basak

Giachino²,

Fiorini³

et al. 2012

J. Neurosci.

155

158

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The adult mammalian forebrain contains neural stem/progenitor cells (NSCs) that generate neurons throughout life. As in other somatic stem cell systems, NSCs are proposed to be predominantly quiescent and proliferate only sporadically to produce more committed progeny. However, quiescence has recently been shown not to be an essential criterion for stem cells. It is not known whether NSCs show differences in molecular dependence based on their proliferation state. The subventricular zone (SVZ) of the adult mouse brain has a remarkable capacity for repair by activation of NSCs. The molecular interplay controlling adult NSCs during neurogenesis or regeneration is not clear but resolving these interactions is critical in order to understand brain homeostasis and repair. Using conditional genetics and fate mapping, we show that Notch signaling is essential for neurogenesis in the SVZ. By mosaic analysis, we uncovered a surprising difference in Notch dependence between active neurogenic and regenerative NSCs. While both active and regenerative NSCs depend upon canonical Notch signaling, Notch1-deletion results in a selective loss of active NSCs (aNSCs). In sharp contrast, quiescent NSCs (qNSCs) remain after Notch1 ablation until induced during regeneration or aging, whereupon they become Notch1-dependent and fail to fully reinstate neurogenesis. Our results suggest that Notch1 is a key component of the adult SVZ niche, promoting maintenance of aNSCs, and that this function is compensated in qNSCs. Therefore, we confirm the importance of Notch signaling for maintaining NSCs and neurogenesis in the adult SVZ and reveal that NSCs display a selective reliance on Notch1 that may be dictated by mitotic state.

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“…Brain damage, such as experimental stroke (Arvidsson et al, 2002) or intrastriatal injection of the excitotoxin quinolinic acid (QA) (Tattersfield et al, 2004) enhances the proliferation of neural stem/progenitor cells (NSPCs) that are located in the subventricular zone (SVZ) or the ependymal cell layer (Carlen et al, 2009). Understanding the cellular mechanisms that regulate the proliferation and differentiation of NSPCs following brain injury is important, as these cells have been suggested to contribute to endogenous brain repair and can constitute a potential source of donor tissue for cell transplantation therapies , Burns et al, 2009).…”

mentioning

confidence: 99%

Brain injury activates microglia that induce neural stem cell proliferation ex vivo and promote differentiation of neurosphere-derived cells into neurons and oligodendrocytes

et al. 2010

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Here, we developed an ex vivo method to investigate how the proliferation of NSPCs changes over time after experimental stroke or excitotoxic striatal lesion in the adult rat brain by studying the effects of microglial cells derived from an injured brain on NSPCs. We isolated NSPCs from the SVZ of brains with lesions and analyzed their growth and differentiation when cultured as neurospheres. We found that NSPCs isolated from the brains 1-2 weeks following injury consistently generated more and larger neurospheres than those harvested from naïve brains. We attributed these effects to the presence of microglial cells in NSPC cultures that originated from injured brains. We suggest that the effects are due to released factors because we observed increased proliferation of NSPCs isolated from non-injured brains when they were exposed to conditioned medium from cultures containing microglial cells derived from injured brains. Furthermore, we found that NSPCs derived from injured brains were more likely to differentiate into neurons and oligodendrocytes than astrocytes. Our ex vivo system reliably mimics what is observed in vivo following brain injury. It constitutes a powerful tool that could be used to identify factors that promote NSPC proliferation and differentiation in response to injury-induced activation of microglial cells, by using tools such as proteomics and gene array technology.4

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Forebrain ependymal cells are Notch-dependent and generate neuroblasts and astrocytes after stroke

Cited by 404 publications

References 43 publications

Generation and characterization of a Notch1 signaling‐specific reporter mouse line

Generation and characterization of a Notch1 signaling‐specific reporter mouse line

Neurogenic Subventricular Zone Stem/Progenitor Cells Are Notch1-Dependent in Their Active But Not Quiescent State

Brain injury activates microglia that induce neural stem cell proliferation ex vivo and promote differentiation of neurosphere-derived cells into neurons and oligodendrocytes

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