Abstract
The postnatal subventricular zone (SVZ) harbors neural stem cells (NSCs) that exhibit robust neurogenesis. However, the epigenetic mechanisms that maintain NSCs and regulate neurogenesis remain unclear. We report that label-retaining SVZ NSCs express Eed, the core component of Polycomb repressive complex 2. In vivo and in vitro conditional knockout and knockdown show Eed is necessary for maintaining NSC proliferation, neurogenesis and neurosphere formation. We discovered that Eed functions to maintain p21 protein levels in NSCs by repressing Gata6 transcription. Both Gata6 overexpression and p21 knockdown reduced neurogenesis, while Gata6 knockdown or p21 overexpression partially rescued neurogenesis after Eed loss. Furthermore, genetic deletion of Eed impaired injury induced SVZ proliferation and emigration. These data reveal a novel epigenetic regulated pathway and suggest an essential role for Eed in SVZ homeostasis and injury.
Highlights
The postnatal/adult subventricular zone (SVZ) harbors the largest population of neural stem cells (NSCs) in the brain (Ihrie and Alvarez-Buylla 2011)
SVZ NSCs self-renew slowly throughout life and generate rapidly dividing transit amplifying progenitors (TAPs), which give rise to neuroblasts that migrate to the olfactory bulbs (OB) in the rostral migratory stream (RMS)
Eed loss and increased Gata6 decreases p21 protein levels. These findings suggest that Eed regulation of Gata6 fine-tunes p21 levels and that this is essential for NSC activation and neurogenesis
Summary
The postnatal/adult subventricular zone (SVZ) harbors the largest population of neural stem cells (NSCs) in the brain (Ihrie and Alvarez-Buylla 2011). SVZ NSCs self-renew slowly throughout life and generate rapidly dividing transit amplifying progenitors (TAPs), which give rise to neuroblasts that migrate to the olfactory bulbs (OB) in the rostral migratory stream (RMS). The SVZ is an excellent system for uncovering developmental mechanisms and has therapeutic relevance, since progenitors migrate to injuries and provide neuroprotection (Pluchino et al 2003; Young et al 2011). Understanding what mechanisms regulate activation of stem cell division and neurogenesis in SVZ cells is a fundamental developmental question which could yield therapeutic approaches SVZ NSCs can become harmful when disruption of tightly regulated SVZ cell cycles leads to gliomagenesis (Sanai et al 2005; Bardella et al 2016).
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