title: DNA Methyltransferase 1 Is Indispensable for Development of the Hippocampal Dentate Gyrus.
abstract: Development of the hippocampal dentate gyrus (DG) in the mammalian brain is achieved through multiple processes during late embryonic and postnatal stages, with each developmental step being strictly governed by extracellular cues and intracellular mechanisms. Here, we show that the maintenance DNA methyltransferase 1 (Dnmt1) is critical for development of the DG in the mouse. Deletion of Dnmt1 in neural stem cells (NSCs) at the beginning of DG development led to a smaller size of the granule cell layer in the DG. NSCs lacking Dnmt1 failed to establish proper radial processes or to migrate into the subgranular zone, resulting in aberrant neuronal production in the molecular layer of the DG and a reduction of integrated neurons in the granule cell layer. Interestingly, prenatal deletion of Dnmt1 in NSCs affected not only the developmental progression of the DG but also the properties of NSCs maintained into adulthood: Dnmt1-deficient NSCs displayed impaired neurogenic ability and proliferation. We also found that Dnmt1 deficiency in NSCs decreased the expression of Reelin signaling components in the developing DG and increased that of the cell cycle inhibitors p21 and p57 in the adult DG. Together, these findings led us to propose that Dnmt1 functions as a key regulator to ensure the proper development of the DG, as well as the proper status of NSCs maintained into adulthood, by modulating extracellular signaling and intracellular mechanisms.
  
  
  
  Here, we provide evidence that Dnmt1 is required for the proper development of the hippocampal dentate gyrus (DG). Deletion of Dnmt1 in neural stem cells (NSCs) at an early stage of DG development impaired the ability of NSCs to establish secondary radial glial scaffolds and to migrate into the subgranular zone of the DG, leading to aberrant neuronal production in the molecular layer, increased cell death, and decreased granule neuron production. Prenatal deletion of Dnmt1 in NSCs also induced defects in the proliferation and neurogenic ability of adult NSCs. Furthermore, we found that Dnmt1 regulates the expression of key extracellular signaling components during developmental stages while modulating intracellular mechanisms for proliferation and neuronal production of NSCs in the adult.
authors.affiliation: Stem Cell Biology and Medicine, Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan, and.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Noguchi
authors.affiliation: Stem Cell Biology and Medicine, Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan, and.
authors.forename: Naoya
authors.initials: N
authors.lastname: Murao
authors.affiliation: Stem Cell Biology and Medicine, Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan, and.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Kimura
authors.affiliation: Stem Cell Biology and Medicine, Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan, and.
authors.forename: Taito
authors.initials: T
authors.lastname: Matsuda
authors.affiliation: Molecular Neurophysiology Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Ibaraki 305-8566, Japan kin1@scb.med.kyushu-u.ac.jp m-namihira@aist.go.jp.
authors.forename: Masakazu
authors.identifier: 0000-0003-2108-5712
authors.initials: M
authors.lastname: Namihira
authors.affiliation: Stem Cell Biology and Medicine, Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan, and kin1@scb.med.kyushu-u.ac.jp m-namihira@aist.go.jp.
authors.forename: Kinichi
authors.initials: K
authors.lastname: Nakashima
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism*; D018891:Dentate Gyrus / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D000089622:Doublecortin Domain Proteins; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000502:physiology; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000502:physiology*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D000091042:Reelin Protein
chemical_list: D000089622:Doublecortin Domain Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D064231:Nestin; D009479:Neuropeptides; D000091042:Reelin Protein; D049452:Green Fluorescent Proteins; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse; C000717128:Reln protein, mouse
keywords: Dnmt1; dentate gyrus; epigenetics