title: Roles of histone H3K27 trimethylase Ezh2 in retinal proliferation and differentiation.
abstract: The histone modification H3K27me3 regulates transcription negatively, and Jmjd3 and Ezh2 demethylate and methylate H3K27me3 and H3K27, respectively. We demonstrated previously that Jmjd3 plays pivotal roles in the differentiation of subsets of bipolar (BP) cells by regulating H3K27me3 levels at the Bhlhb4 and Vsx1 loci, both of which are transcription factors essential for the maturation of BP cell subsets. In this study, we examined the role of Ezh2 in retinal development using retina-specific Ezh2 conditional knockout mice (Ezh2-CKO). The eyes of the Ezh2-CKO mice were microphthalemic, and the proliferation of retinal cells was diminished postnatally in Ezh2-CKO. Differentiation of all examined retinal subsets was observed with higher proportion of BP cell subsets, which was determined by immunostaining using specific retinal markers. The onsets of Müller glia and rod photoreceptor differentiation were accelerated. The expression of Bhlhb4 was increased in postnatal retinas, which was accompanied by the loss of H3K27me3 modifications at these genetic loci. Decreased expression of proneural genes in postnatal stage was observed. As reported previously in other Ezh2-KO tissues, increased expression of Arf/Ink4a was observed in the Ezh2-CKO retinas. The ectopic expression of Arf or Ink4a in the retina suppressed proliferation and increased apoptosis. In addition, earlier onset of Müller glia differentiation was observed in Ink4a-expressing cells. These results support an important role for histone H3K27me3 modification in regulating the proliferation and maturation of certain subsets of interneurons in the retina.
authors.affiliation: Division of Molecular and Developmental Biology, Institute of Medical Science, University of Tokyo, Tokyo.
authors.forename: Atsumi
authors.initials: A
authors.lastname: Iida
authors.affiliation: Division of Molecular and Developmental Biology, Institute of Medical Science, University of Tokyo, Tokyo.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Iwagawa
authors.affiliation: Division of Molecular and Developmental Biology, Institute of Medical Science, University of Tokyo, Tokyo.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Baba
authors.affiliation: Division of Molecular and Developmental Biology, Institute of Medical Science, University of Tokyo, Tokyo.
authors.forename: Shinya
authors.initials: S
authors.lastname: Satoh
authors.affiliation: Division of Molecular and Developmental Biology, Institute of Medical Science, University of Tokyo, Tokyo.|Department of Ophthalmology, Graduate School of Medicine, Juntendo University, Tokyo.
authors.forename: Yujin
authors.initials: Y
authors.lastname: Mochizuki
authors.affiliation: Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakauchi
authors.affiliation: Laboratory for Molecular and Developmental Biology, Institute for Protein Research, Osaka University, Osaka.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Furukawa
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Center for Allergy and Immunology, Kanagawa.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.affiliation: Department of Ophthalmology, Graduate School of Medicine, Juntendo University, Tokyo.
authors.forename: Akira
authors.initials: A
authors.lastname: Murakami
authors.affiliation: Division of Molecular and Developmental Biology, Institute of Medical Science, University of Tokyo, Tokyo.
authors.forename: Sumiko
authors.initials: S
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D007395:Interneurons / Q000473:pathology / Q000502:physiology; D018345:Mice, Knockout; D055495:Neurogenesis / Q000502:physiology*; D009457:Neuroglia / Q000473:pathology / Q000502:physiology; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D012160:Retina / Q000254:growth & development* / Q000473:pathology / Q000502:physiology*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2
keywords: differentiation; histone methylation; proliferation; retina