title: Prdm16 is crucial for progression of the multipolar phase during neural differentiation of the developing neocortex.
abstract: The precise control of neuronal migration and morphological changes during differentiation is essential for neocortical development. We hypothesized that the transition of progenitors through progressive stages of differentiation involves dynamic changes in levels of mitochondrial reactive oxygen species (mtROS), depending on cell requirements. We found that progenitors had higher levels of mtROS, but that these levels were significantly decreased with differentiation. The Prdm16 gene was identified as a candidate modulator of mtROS using microarray analysis, and was specifically expressed by progenitors in the ventricular zone. However, Prdm16 expression declined during the transition into NeuroD1-positive multipolar cells. Subsequently, repression of Prdm16 expression by NeuroD1 on the periphery of ventricular zone was crucial for appropriate progression of the multipolar phase and was required for normal cellular development. Furthermore, time-lapse imaging experiments revealed abnormal migration and morphological changes in Prdm16-overexpressing and -knockdown cells. Reporter assays and mtROS determinations demonstrated that PGC1α is a major downstream effector of Prdm16 and NeuroD1, and is required for regulation of the multipolar phase and characteristic modes of migration. Taken together, these data suggest that Prdm16 plays an important role in dynamic cellular redox changes in developing neocortex during neural differentiation.
authors.affiliation: Laboratory of Neural Differentiation, Graduate School of Brain Science, Doshisha University, Kyoto 6190225, Japan.
authors.forename: Mayuko
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Laboratory of Neural Differentiation, Graduate School of Brain Science, Doshisha University, Kyoto 6190225, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Iwai
authors.affiliation: Department of Molecular Neurobiology, Institute for Developmental Research, Kasugai, Aichi 4800392, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Tabata
authors.affiliation: Laboratory for Cell Asymmetry, Center for Developmental Biology, RIKEN Kobe Institute, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Daijiro
authors.initials: D
authors.lastname: Konno
authors.affiliation: Laboratory of Neural Differentiation, Graduate School of Brain Science, Doshisha University, Kyoto 6190225, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Komabayashi-Suzuki
authors.affiliation: Laboratory of Neural Differentiation, Graduate School of Brain Science, Doshisha University, Kyoto 6190225, Japan.
authors.forename: Chisato
authors.initials: C
authors.lastname: Watanabe
authors.affiliation: Department of Quantitative Biology and Medicine, RCAST, The University of Tokyo, Tokyo 1538904, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Iwanari
authors.affiliation: Department of Quantitative Biology and Medicine, RCAST, The University of Tokyo, Tokyo 1538904, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Mochizuki
authors.affiliation: Department of Quantitative Biology and Medicine, RCAST, The University of Tokyo, Tokyo 1538904, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Hamakubo
authors.affiliation: Laboratory for Cell Asymmetry, Center for Developmental Biology, RIKEN Kobe Institute, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Matsuzaki
authors.affiliation: Department of Molecular Neurobiology, Institute for Developmental Research, Kasugai, Aichi 4800392, Japan.
authors.forename: Koh-Ichi
authors.initials: KI
authors.lastname: Nagata
authors.affiliation: Laboratory of Neural Differentiation, Graduate School of Brain Science, Doshisha University, Kyoto 6190225, Japan kmizutan@mail.doshisha.ac.jp.|PRESTO "Development and Function of Neural Networks", Japan Science and Technology Agency, Saitama 3320012, Japan.
authors.forename: Ken-Ichi
authors.identifier: 0000-0001-6007-1132
authors.initials: KI
authors.lastname: Mizutani
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D019579:Neocortex / Q000166:cytology / Q000196:embryology* / Q000502:physiology; D058953:Neural Stem Cells / Q000166:cytology* / Q000502:physiology*; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology; D010084:Oxidation-Reduction; D011247:Pregnancy; D017382:Reactive Oxygen Species / Q000378:metabolism; D059008:Time-Lapse Imaging; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C501008:Neurod1 protein, mouse; C521133:Prdm16 protein, mouse
keywords: Mouse; Multipolar phase; Neocortical development; Neural differentiation; Neural stem cells; NeuroD1; Prdm16