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Abstract
BackgroundPrecise spatiotemporal control of gene expression is essential for the establishment of correct cell numbers and identities during brain development. This process involves epigenetic control mechanisms, such as those mediated by the polycomb group protein Ezh2, which catalyzes trimethylation of histone H3K27 (H3K27me3) and thereby represses gene expression.ResultsHerein, we show that Ezh2 plays a crucial role in the development and maintenance of the midbrain. Conditional deletion of Ezh2 in the developing midbrain resulted in decreased neural progenitor proliferation, which is associated with derepression of cell cycle inhibitors and negative regulation of Wnt/β-catenin signaling. Of note, Ezh2 ablation also promoted ectopic expression of a forebrain transcriptional program involving derepression of the forebrain determinants Foxg1 and Pax6. This was accompanied by reduced expression of midbrain markers, including Pax3 and Pax7, as a consequence of decreased Wnt/β-catenin signaling.ConclusionEzh2 is required for appropriate brain growth and maintenance of regional identity by H3K27me3-mediated gene repression and control of canonical Wnt signaling.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-015-0210-9) contains supplementary material, which is available to authorized users.
Highlights
Precise spatiotemporal control of gene expression is essential for the establishment of correct cell numbers and identities during brain development
A role of polycomb group (PcG) proteins in the developing nervous system was suggested by experiments in embryonic stem cells undergoing neural differentiation, in which genes active during neurogenesis were shown to be dynamically marked by H3K27me3 and interference with demethylation of H3K27me3 prevented proper acquisition of a neural fate [1, 6, 7]
Conditional inactivation of enhancer of zeste homolog 2 (Ezh2) in the developing midbrain affects progenitor cell expansion To address the role of Ezh2-mediated H3K27me3 in the developing midbrain, we conditionally deleted Ezh2 in mice homozygous for the floxed allele of Ezh2 using the Wnt1-Cre allele (Fig. 1a) [10, 12]
Summary
Precise spatiotemporal control of gene expression is essential for the establishment of correct cell numbers and identities during brain development This process involves epigenetic control mechanisms, such as those mediated by the polycomb group protein Ezh, which catalyzes trimethylation of histone H3K27 (H3K27me3) and thereby represses gene expression. Fate switches associated, for instance, with the transition from a proliferative multipotent progenitor cell to a non-dividing terminally differentiated cell type, are accompanied and potentially controlled by changes in epigenetic information Key players in this process are polycomb group (PcG) proteins that form two complexes, polycomb repressive complex (PRC) 1 and PRC2, which repress gene activity by catalyzing trimethylation of lysine 27 on histone H3 (H3K27me3) [2, 3]. Conditional knock out (cko) of Ezh in the developing murine forebrain around embryonic day (E) 10, i.e. before onset of neurogenesis, shifted the balance between self-renewal and differentiation of neural progenitors cells (NPCs) towards
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