title: Mammalian Gcm genes induce Hes5 expression by active DNA demethylation and induce neural stem cells.
abstract: Signaling mediated by Notch receptors is crucial for the development of many organs and the maintenance of various stem cell populations. The activation of Notch signaling is first detectable by the expression of an effector gene, Hes5, in the neuroepithelium of mouse embryos at embryonic day (E) 8.0-8.5, and this activation is indispensable for the generation of neural stem cells. However, the molecular mechanism by which Hes5 expression is initiated in stem-producing cells remains unknown. We found that mammalian Gcm1 and Gcm2 (glial cells missing 1 and 2) are involved in the epigenetic regulation of Hes5 transcription by DNA demethylation independently of DNA replication. Loss of both Gcm genes and subsequent lack of Hes5 upregulation in the neuroepithelium of E7.5-8.5 Gcm1(-/-); Gcm2(-/-) mice resulted in the impaired induction of neural stem cells. Our data suggest that Hes5 expression is serially activated first by Gcms and later by the canonical Notch pathway.
authors.affiliation: Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, Japan. shitoshi-tky@umin.ac.jp
authors.forename: Seiji
authors.initials: S
authors.lastname: Hitoshi
authors.forename: Yugo
authors.initials: Y
authors.lastname: Ishino
authors.forename: Akhilesh
authors.initials: A
authors.lastname: Kumar
authors.forename: Salma
authors.initials: S
authors.lastname: Jasmine
authors.forename: Kenji F
authors.initials: KF
authors.lastname: Tanaka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kondo
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Hosoya
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Hotta
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ikenaka
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001921:Brain / Q000196:embryology / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D047369:Chromatin Immunoprecipitation / Q000379:methods; D003001:Cloning, Molecular / Q000379:methods; D003570:Cytidine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins; D018274:Electroporation / Q000379:methods; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000187:drug effects / Q000502:physiology*; D009479:Neuropeptides / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D001374:Azacitidine; D051792:Basic Helix-Loop-Helix Proteins; D001973:Bromodeoxyuridine; D003570:Cytidine Triphosphate; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D049452:Green Fluorescent Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; D012333:RNA, Messenger; D051880:Receptors, Notch; D012097:Repressor Proteins; D014157:Transcription Factors; C101631:Gcm1 protein, mouse; C523486:Gcm2 protein, mouse; C489685:Hes5 protein, mouse; C038673:5-aza-2'-deoxycytidine-5'-triphosphate