Distinct and separable roles for EZH2 in neurogenic astroglia

Hwang, William W.; Salinas, Ryan; Siu, Jason J.; Kelley, Kevin W.; Delgado, Ryan N.; Paredes, Mercedes F.; Alvarez-Buylla, Arturo; Oldham, Michael C.; Lim, Daniel A.

doi:10.7554/elife.02439

Cited by 65 publications

(74 citation statements)

References 61 publications

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“…Endothelial cells also secrete neurotrophin-3 (NT-3), and NT-3 signaling in V-SVZ NSCs causes the rapid phosphorylation of endothelial nitric oxide synthase (NOS), leading to the production of nitric oxide (NO), which acts as a cytostatic factor (Delgado et al 2014). Thus, these data indicate that endothelial cells also control adult V-SVZ neurogenesis at perhaps the earliest stage of the neuronal lineage, regulating the quiescence of the NSC population.…”

Section: Mitogens and Growth Factors Of The V-svzmentioning

confidence: 99%

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The Adult Ventricular–Subventricular Zone (V-SVZ) and Olfactory Bulb (OB) Neurogenesis

Lim

Alvarez-Buylla

2016

Cold Spring Harb Perspect Biol

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A large population of neural stem/precursor cells (NSCs) persists in the ventricular-subventricular zone (V-SVZ) located in the walls of the lateral brain ventricles. V-SVZ NSCs produce large numbers of neuroblasts that migrate a long distance into the olfactory bulb (OB) where they differentiate into local circuit interneurons. Here, we review a broad range of discoveries that have emerged from studies of postnatal V-SVZ neurogenesis: the identification of NSCs as a subpopulation of astroglial cells, the neurogenic lineage, new mechanisms of neuronal migration, and molecular regulators of precursor cell proliferation and migration. It has also become evident that V-SVZ NSCs are regionally heterogeneous, with NSCs located in different regions of the ventricle wall generating distinct OB interneuron subtypes. Insights into the developmental origins and molecular mechanisms that underlie the regional specification of V-SVZ NSCs have also begun to emerge. Other recent studies have revealed new cellintrinsic molecular mechanisms that enable lifelong neurogenesis in the V-SVZ. Finally, we discuss intriguing differences between the rodent V-SVZ and the corresponding human brain region. The rapidly expanding cellular and molecular knowledge of V-SVZ NSC biology provides key insights into postnatal neural development, the origin of brain tumors, and may inform the development regenerative therapies from cultured and endogenous human neural precursors. N ew neurons continue to be added throughout life to the olfactory bulb (OB) in the brain of many mammals. In rodents, the adult germinal region for OB neurogenesis is located along the walls of the brain lateral ventricles. Recent results regarding the spatial arrangement and cellular morphology of the primary neural precursors-or, neural stem cells (NSCs)-indicate that this region has characteristics similar to both the embryonic ventricular zone (VZ) and subventricular zone (SVZ). Given this new understanding, we now refer to this region as the ventricular-subventricular zone (V-SVZ).Neuroblasts born from NSCs in the mouse V-SVZ migrate rostrally into the OB where they then disperse radially and differentiate into functional interneurons (Fig. 1). Several distinct interneuron subtypes are generated by the V-SVZ, and estimates indicate that thousands of new OB neurons are generated every day in the young adult rodent brain.

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Section: Mitogens and Growth Factors Of The V-svzmentioning

confidence: 99%

“…During postnatal development, EZH2 become restricted to adult NSCs and their daughter cells (Hwang et al 2014). EZH2 expression thus appears to distinguish neurogenic astroglial cells from nonneurogenic astrocytes in the postnatal mouse and human brain.…”

Section: Polycomb Group and Trithorax Group Chromatin-modifying Factomentioning

confidence: 99%

The Adult Ventricular–Subventricular Zone (V-SVZ) and Olfactory Bulb (OB) Neurogenesis

Lim

Alvarez-Buylla

2016

Cold Spring Harb Perspect Biol

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491

428

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“…Consistent with this hypothesis, Ezh2 enhanced the neurogenic competence of adult subventricular NSCs by the direct repression of Olig2 (encoding oligodendrocyte lineage transcription factor, a bHLH protein). At the same time, Ezh2 prevented the aberrant activation of many homeodomain containing transcriptional regulators specifying non-SVZ neuronal subtypes [87].…”

Section: Polycomb Group Complexes In Adult Nscsmentioning

confidence: 99%

“…Subventricular NSCs resemble RGCs and show a sustained expression of Ezh2 [87], pointing to additional tasks. In support of this view, Ezh2 sustains self-renewal of subventricular NSCs by direct repression of the cyclin-dependent kinase inhibitor (CDKI) 2a (hereafter Ink4a/Arf), which generates through the use of shared coding regions and alternative reading frames the two major proteins p16 ink4a and p19 arf .…”

Section: Polycomb Group Complexes In Adult Nscsmentioning

confidence: 99%

Switch-Like Roles for Polycomb Proteins from Neurodevelopment to Neurodegeneration

et al. 2017

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Polycomb Group (PcG) proteins are best-known for maintaining repressive or active chromatin states that are passed on across multiple cell divisions, and thus sustain long-term memory of gene expression. PcG proteins engage different, partly gene-and/or stage-specific, mechanisms to mediate spatiotemporal gene expression during central nervous system development. In the course of this, PcG proteins bind to various cis-regulatory sequences (e.g., promoters, enhancers or silencers) and coordinate, as well the interactions between distantly separated genomic regions to control chromatin function at different scales ranging from compaction of the linear chromatin to the formation of topological hubs. Recent findings show that PcG proteins are involved in switch-like changes in gene expression states of selected neural genes during the transition from multipotent to differentiating cells, and then to mature neurons. Beyond neurodevelopment, PcG proteins sustain mature neuronal function and viability, and prevent progressive neurodegeneration in mice. In support of this view, neuropathological findings from human neurodegenerative diseases point to altered PcG functions. Overall, improved insight into the multiplicity of PcG functions may advance our understanding of human neurodegenerative diseases and ultimately pave the way to new therapies.

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“…Since Nox4 enzyme activity seems to be regulated at the transcriptional level [24], the upregulation of the Nox4 gene might result in an increase in total Nox4 enzymatic activity followed by an increase of ROS production. Epigenetic regulation of the Nox4 gene in other cell systems has been reported [23,34] and histone modifications have been demonstrated to be key factors in neurogenesis of SVZ NSCs [10,20]. Therefore, it will be worth studying epigenetic regulation of the Nox4 gene during neuronal differentiation.…”

Section: Inhibition Of Neurogenesis By Knockdown Of Nox4mentioning

confidence: 99%

Role of Nox4 in Neuronal Differentiation of Mouse Subventricular Zone Neural Stem Cells

Park¹,

Na²,

Kim³

2016

Journal of Life Science

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Reactive oxygen species (ROS), at appropriate concentrations, mediate various normal cellular functions, including defense against pathogens, signal transduction, cellular growth, and gene expression. A recent study demonstrated that ROS and ROS-generating NADPH oxidase (Nox) are important in self-renewal and neuronal differentiation of subventricular zone (SVZ) neural stem cells in adult mouse brains. In this study, we found that endogenous ROS were detected in SVZ neural stem cells cultured from postnatal mouse brains. Nox4 was predominantly expressed in cultured cells, while the levels of the Nox1 and Nox2 transcripts were very low. In addition, the Nox4 gene was highly upregulated (by up to 10-fold) during neuronal differentiation. Immunocytochemical analysis detected the Nox4 protein mainly in neurons positive for the neuronal specific tubulin Tuj1. After differentiation, endogenous ROS were detected exclusively in neuron-like cells with processes. In addition, perturbation of the cellular redox state with N-acetyl cysteine, a ROS scavenger, during neuronal differentiation greatly inhibited neurogenesis. Lastly, knockdown of Nox4 using short hairpin RNA decreased neurogenesis. These findings suggest that Nox4 may be a major ROS-generating enzyme in postnatal SVZ neural stem cells, and Nox4-mediated ROS generation may be important in their neuronal differentiation.

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Distinct and separable roles for EZH2 in neurogenic astroglia

Cited by 65 publications

References 61 publications

The Adult Ventricular–Subventricular Zone (V-SVZ) and Olfactory Bulb (OB) Neurogenesis

The Adult Ventricular–Subventricular Zone (V-SVZ) and Olfactory Bulb (OB) Neurogenesis

Switch-Like Roles for Polycomb Proteins from Neurodevelopment to Neurodegeneration

Role of Nox4 in Neuronal Differentiation of Mouse Subventricular Zone Neural Stem Cells

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