Loss of Ezh2 promotes a midbrain-to-forebrain identity switch by direct gene derepression and Wnt-dependent regulation

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.

EZH2 influences mdDA neuronal differentiation, maintenance and survival

“…Matching results were obtained for the dorsal midbrain, where the loss of Ezh2 leads to a reduced neuroepithelial thickness, by negatively affecting proliferation and canonical Wnt-signaling (Zemke et al, 2015). To study whether Ezh2 affects the differentiation of mdDA neurons we crossed Ezh2-floxed mice (Shen et al, 2008) with En1Cre animals (Kimmel et al, 2000), deleting Ezh2 from ventral midbrain progenitors from E10.5 onward (Sunmonu et al, 2009;Zemke et al, 2015). As described above, EZH2 is the methyltransferase of PRC2, which catalyzes the methylation of H3K27 (Cao and Zhang, 2004a;Margueron et al, 2008;Shen et al, 2008) and in previous studies in which Ezh2 is conditionally removed from neuronal progenitors a widespread loss of H3K27me3 is observed (Hirabayashi et al, 2009;Pereira et al, 2010;Zemke et al, 2015).…”

“…Previous studies have shown that the conditional deletion of Ezh2 in neuronal progenitors shift the balance between self-renewal and differentiation, in favor of differentiation (Feng et al, 2016;Pereira et al, 2010;Zemke et al, 2015). Conditional deletion of Ezh2 in cortical progenitors showed that an increased fraction of cortical progenitors leave the cell cycle at an earlier time-point, leading to a substantial thinner cortex (Pereira et al, 2010).…”

“…To study whether Ezh2 affects the differentiation of mdDA neurons we crossed Ezh2-floxed mice (Shen et al, 2008) with En1Cre animals (Kimmel et al, 2000), deleting Ezh2 from ventral midbrain progenitors from E10.5 onward (Sunmonu et al, 2009;Zemke et al, 2015). As described above, EZH2 is the methyltransferase of PRC2, which catalyzes the methylation of H3K27 (Cao and Zhang, 2004a;Margueron et al, 2008;Shen et al, 2008) and in previous studies in which Ezh2 is conditionally removed from neuronal progenitors a widespread loss of H3K27me3 is observed (Hirabayashi et al, 2009;Pereira et al, 2010;Zemke et al, 2015). To determine whether En1Cre driven deletion of Ezh2 affects the presence of H3K27me3 we performed immunohistochemistry experiments for H3K27Me3 at E14.5.…”

“…A similar role for Ezh2 was found in neuronal progenitors (NPs) of the dorsal midbrain. Wnt1Cre driven deletion of Ezh2 led to reduced number of NPs in the dorsal midbrain, due to elevated cell cycle exit and differentiation (Zemke et al, 2015). In addition to a role in neuronal development, Ezh2 has also been linked to several neurodegenerative disorders (Li et al, 2013;von Schimmelmann et al, 2016;Södersten et al, 2014).…”

The Role of Epigenetic Mechanisms in the Regulation of Gene Expression in the Nervous System

“…Gene regulatory processes that play a pivotal role in neuronal specification include the epigenetic silencing of non-neuronal/other neuron fatedetermining genes. Much of the negative gene regulation in developing neurons is achieved by the PRC2 (Hirabayashi et al, 2009;Pereira et al, 2010;Di Meglio et al, 2013;Corley and Kroll, 2015;Zemke et al, 2015). While tremendous progress has been made in elucidating the role of PRC2 in neuronal specification during development (Corley and Kroll, 2015), little is known about the role of PRC2 in the adult brain.…”