Notch Signaling Is Required to Maintain All Neural Stem Cell Populations – Irrespective of Spatial or Temporal Niche

Alexson, Tania O.; Hitoshi, Seiji; Coles, Brenda L.K.; Bernstein, Alan; Kooy, Derek van der

doi:10.1159/000090751

Cited by 98 publications

(76 citation statements)

References 82 publications

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“…Most notably, Notch signaling regulates stem cell numbers (29) and can increase proliferation in the SVZ by maintaining expression of the multi-/pluripotency transcription factor Sox2, which regulates expression of Sonic hedgehog, which is required for survival and normal proliferation (29)(30)(31)(32). Although activation of Notch modulates cell cycle time (33), it also leads to repression of proneural gene expression and maintenance, specifically of the NSC (34)(35)(36). In keeping, enhanced Notch signaling by the vascular niche factor pigment epithelium-derived factor diverts asymmetrical division to production of two self-renewing NSCs in the adult brain (37).…”

Section: Discussionmentioning

confidence: 99%

Cell cycle restriction by histone H2AX limits proliferation of adult neural stem cells

Fernando

Eleuteri

Abdelhady

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

137

118

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Adult neural stem cell proliferation is dynamic and has the potential for massive self-renewal yet undergoes limited cell division in vivo. Here, we report an epigenetic mechanism regulating proliferation and self-renewal. The recruitment of the PI3K-related kinase signaling pathway and histone H2AX phosphorylation following GABA A receptor activation limits subventricular zone proliferation. As a result, NSC self-renewal and niche size is dynamic and can be directly modulated in both directions pharmacologically or by genetically targeting H2AX activation. Surprisingly, changes in proliferation have long-lasting consequences on stem cell numbers, niche size, and neuronal output. These results establish a mechanism that continuously limits proliferation and demonstrates its impact on adult neurogenesis. Such homeostatic suppression of NSC proliferation may contribute to the limited selfrepair capacity of the damaged brain.DNA damage response | subventricular zone astrocytes | self-repair

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Section: Discussionmentioning

confidence: 99%

Cell cycle restriction by histone H2AX limits proliferation of adult neural stem cells

Fernando

Eleuteri

Abdelhady

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

137

118

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“…PS1-mutant mice die in utero with a phenotype similar to that observed for Notch signaling mutants [131 -133]. However, PS1 +/-mice survive to adulthood but show a decreased neurogenesis in the SEZ and a reduction in spherogenic cells [134,135]. Similarly, pharmacological inhibition of PS-activity results in reduced proliferation and increased cell death in SEZ-derived progenitors [136].…”

Section: Notch and Lateral Signaling During Adult Neurogenesismentioning

confidence: 98%

Stem cells of the adult mammalian brain and their niche

Basak

Taylor

2008

Cell. Mol. Life Sci.

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Abstract. The mammalian brain is a paradox of evolution. Although the advance in complexity of the human brain has exceeded the development of other organs, it has practically lost the ability to regenerate, and damage is repaired mainly by functional plasticity. This disparity is, however, not due to the lack of progenitor cells in the adult mammalian brain, but to their diminished or repressed capacity to replace neurons in most brain regions. Here, we discuss the current literature describing the processes of neurogenesis in the adult mammalian brain, and the recent advances in adult neural stem cells (aNSCs) with a focus on their identity, cell cycle and niche signals. Understanding these processes may hopefully lead to therapies in the future to reinstate self-repair of the brain from endogenous progenitors.Keywords. Neural stem cells, neurogenesis, stem cell niche, adult brain, subventricular zone. The discovery of neurogenesis in the adult brainNSCs are the foundations of the brain during development, and despite poor regenerative capacity, they persist in the mammalian brain throughout postnatal development and into adulthood and continue to generate neurons. aNSCs self-renew and retain multipotency in almost all mammalian species analyzed, including humans. NSCs reside in specialized germinal layers where multiple cell-types interact with them and contribute to generate niches that control their fate choices and permit neurogenesis. Genetic and functional analyses have revealed roles for several genes and signaling pathways in controlling adult neurogenesis. However, the identities of the stem cells in the brain remain elusive, which presents an elementary problem for the interpretation of these results. In attempts to identify aNSCs, several groups have defined populations that contain cells with stem cell features, although unambiguous markers are still missing. Given their potential as putative tools for cell-based therapies, elucidating the molecular pathways that identify aNSCs and govern their cell fate is essential. Neurons in most regions of the adult mammalian brain are generated from NSCs and restricted progenitors during embryonic development before a switch to gliogenesis in peri-and postnatal development [1]. As early as the 1960s and 70s, newly generated neurons were identified by nucleotide analogue incorporation assays in adult rodents [2, 3]. These results, however, met with skepticism due to the poor regenerative capacity of the mammalian brain. Detailed studies went on to show extensive neurogenesis in the vocal control center in the brains of adult canaries, which correlates with seasonal song learning [4,5]. After a brief re-visitation to the topic in the mid-1980s, it was the use of retroviral lineage tracing assays that identified newborn neurons in the adult mammalian brain. These findings were quickly followed by the identification of zones with neurogenic capacity in

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“…together to prevent terminal differentiation and to preserve a pool of stem cells (Alexson et al, 2006). Notch signaling is thought to maintain ''stemness'' and to prevent exit from the cell cycle and maturation (Basak and Taylor, 2009).…”

Section: Developmental Dynamicsmentioning

confidence: 99%

Endothelial cells promote neural stem cell proliferation and differentiation associated with VEGF activated Notch and Pten signaling

Sun

Zhou

et al. 2010

Developmental Dynamics

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To investigate whether and how endothelial cells affect neurogenesis, we established a system to co-culture endothelial cells and brain slices of neonatal rat and observed how subventricular zone cells differentiate in the presence of endothelial cells. In the presence of endothelial cells, neural stem cells increased in number, as did differentiated neurons and glia. The augmentation of neurogenesis was reversed by diminishing vascular endothelial growth factor (VEGF) expression in endothelial cells with RNA interference (RNAi). Microarray analysis indicated that expression levels of 112 genes were significantly altered by co-culture and that expression of 81 of the 112 genes recovered to normal levels following RNAi of VEGF in endothelial cells. Pathway mapping showed an enrichment of genes in the Notch and Pten pathways. These data indicate that endothelial cells promote neural stem cell proliferation and differentiation associated with VEGF, possibly by activating the Notch and Pten pathways. Developmental Dynamics 239:2345-2353,

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Notch Signaling Is Required to Maintain All Neural Stem Cell Populations – Irrespective of Spatial or Temporal Niche

Cited by 98 publications

References 82 publications

Cell cycle restriction by histone H2AX limits proliferation of adult neural stem cells

Cell cycle restriction by histone H2AX limits proliferation of adult neural stem cells

Stem cells of the adult mammalian brain and their niche

Endothelial cells promote neural stem cell proliferation and differentiation associated with VEGF activated Notch and Pten signaling

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