title: Loss of Ezh2 promotes a midbrain-to-forebrain identity switch by direct gene derepression and Wnt-dependent regulation.
abstract: BACKGROUND
  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 Ezh2, which catalyzes trimethylation of histone H3K27 (H3K27me3) and thereby represses gene expression.
  
  
  RESULTS
  Herein, 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.
  
  
  CONCLUSIONS
  Ezh2 is required for appropriate brain growth and maintenance of regional identity by H3K27me3-mediated gene repression and control of canonical Wnt signaling.
authors.affiliation: Institute of Anatomy, University of Zürich, Zürich, Switzerland. martina.zemke@anatom.uzh.ch.
authors.forename: Martina
authors.initials: M
authors.lastname: Zemke
authors.affiliation: Institute of Anatomy, University of Zürich, Zürich, Switzerland. kalina.draganova@helmholtz-muenchen.de.
authors.forename: Kalina
authors.initials: K
authors.lastname: Draganova
authors.affiliation: Institute of Anatomy, University of Zürich, Zürich, Switzerland. annika.klug@uzh.ch.
authors.forename: Annika
authors.initials: A
authors.lastname: Klug
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. anne.schoeler@helmholtz-muenchen.de.
authors.forename: Anne
authors.initials: A
authors.lastname: Schöler
authors.affiliation: Institute of Anatomy, University of Zürich, Zürich, Switzerland. luis.zurkirchen@uzh.ch.
authors.forename: Luis
authors.initials: L
authors.lastname: Zurkirchen
authors.affiliation: Institute of Anatomy, University of Zürich, Zürich, Switzerland. max.g@unibas.ch.
authors.forename: Max Hans-Peter
authors.initials: MH
authors.lastname: Gay
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zürich, Switzerland. Phil.Cheng@usz.ch.
authors.forename: Phil
authors.initials: P
authors.lastname: Cheng
authors.affiliation: RIKEN Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Yokohama, Japan. koseki@rcai.riken.go.jp.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.affiliation: Institute of Molecular Life Sciences, University of Zürich, Zürich, Switzerland. tomas.valenta@imls.uzh.ch.
authors.forename: Tomas
authors.initials: T
authors.lastname: Valenta
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. Dirk.Schubeler@fmi.ch.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schübeler
authors.affiliation: Institute of Molecular Life Sciences, University of Zürich, Zürich, Switzerland. konrad.basler@imls.uzh.ch.
authors.forename: Konrad
authors.initials: K
authors.lastname: Basler
authors.affiliation: Institute of Anatomy, University of Zürich, Zürich, Switzerland. lukas.sommer@anatom.uzh.ch.
authors.forename: Lukas
authors.initials: L
authors.lastname: Sommer
mesh_terms: D000818:Animals; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D008636:Mesencephalon / Q000196:embryology / Q000254:growth & development*; D051379:Mice; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000378:metabolism; D016548:Prosencephalon / Q000196:embryology / Q000254:growth & development*; D060449:Wnt Signaling Pathway
chemical_list: D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2