Updated on 2024/07/13

写真a

 
BIZEN Norihisa
 
Organization
Academic Assembly Institute of Medicine and Dentistry IGAKU KEIRETU Assistant Professor
Graduate School of Medical and Dental Sciences Biological Functions and Medical Control Regenerative and Transplant Medicine Assistant Professor
Title
Assistant Professor
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Degree

  • 博士(医学) ( 2013.3   東京医科歯科大学 )

Research Interests

  • 神経解剖学

  • アストロサイト

  • グリア

  • 神経発生

  • 神経幹細胞

  • オリゴデンドロサイト

  • Olig2

Research Areas

  • Life Science / Anatomy and histopathology of nervous system

  • Life Science / Neuroscience-general

  • Life Science / Anatomy

  • Life Science / Developmental biology

Research History (researchmap)

  • 新潟大学 大学院医歯学総合研究科   脳機能形態学分野   医学部准教授

    2022.10

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  • 新潟大学 大学院医歯学総合研究科 脳機能形態学分野 助教 (分野名変更)

    2021.4

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  • Niigata University   Graduate School of Medical and Dental Sciences   Assistant Professor

    2015.6

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  • Niigata University   Graduate School of Medical and Dental Sciences

    2014.4 - 2015.5

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  • Tokyo Medical and Dental University   Medical Research Institute   Specially Appointed Assistant Professor

    2014.1 - 2014.3

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  • Tokyo Medical and Dental University   Medical Research Institute

    2013.4 - 2013.12

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Research History

  • Niigata University   Graduate School of Medical and Dental Sciences Biological Functions and Medical Control Regenerative and Transplant Medicine   Assistant Professor

    2015.6

Education

  • Tokyo Medical and Dental University   Graduate School of Medical and Dental Sciences

    - 2013.3

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  • Kumamoto University   School of Pharmacy   薬科学科

    - 2007.3

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Professional Memberships

 

Papers

  • Attenuated cerebellar phenotypes in Inpp4a truncation mutants with preserved phosphatase activity. Reviewed International journal

    Dang Minh Tran, Nozomu Yoshioka, Norihisa Bizen, Yukiko Mori-Ochiai, Masato Yano, Shogo Yanai, Junya Hasegawa, Satoshi Miyashita, Mikio Hoshino, Junko Sasaki, Takehiko Sasaki, Hirohide Takebayashi

    Disease models & mechanisms   16 ( 7 )   2023.7

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    Phosphoinositides (PIPs) act as intracellular signaling molecules that regulate various cellular processes. Abnormalities in PIP metabolism cause various pathological conditions, including neurodegenerative diseases, cancer, and immune disorders. Several neurological diseases with diverse phenotypes, such as ataxia with cerebellar atrophy or intellectual disability without brain malformation, are caused by mutations in INPP4A, which encodes a phosphoinositide phosphatase. This study examined two strains of Inpp4a mutant mice with distinct cerebellar phenotypes: the first Inpp4aΔEx1,2 mutant exhibited striatal degeneration without cerebellar atrophy, and the other Inpp4aΔEx23 mutant exhibited a severe striatal phenotype with cerebellar atrophy. Both strains exhibited reduced expressions of Inpp4a mutant proteins in the cerebellum. N-terminal truncated Inpp4a proteins were expressed from Inpp4aΔEx1,2 allele by alternative translation initiation and had phosphatase activity for PI(3,4)P2, whereas the Inpp4a mutant protein encoded by Inpp4aΔEx23 completely lacked phosphatase activity. The diverse phenotypes observed in Inpp4a-related neurological diseases could be due to the varying protein expression levels and retained phosphatase activity in different Inpp4a variants. These findings provide insights into the role of Inpp4a mutations in disease pathogenesis and may help to develop personalized therapy.

    DOI: 10.1242/dmm.050169

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  • Brain-specific glycosylation of protein tyrosine phosphatase receptor type Z (PTPRZ) marks a demyelination-associated astrocyte subtype. Reviewed International journal

    Kazuto Takahashi, Kenji Kanekiyo, Kanoko Sakuda, Yui Muto, Masahiro Iguchi, Nozomu Matsuda, Yuko Hashimoto, Kazuaki Kanai, Haruko Ogawa, Hajime Hirase, Akiyoshi Kakita, Norihisa Bizen, Hirohide Takebayashi, Yasushi Kawaguchi, Miwa Uzuki, Shinobu Kitazume

    Journal of neurochemistry   166 ( 3 )   547 - 559   2023.4

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    Astrocytes are the most abundant glial cell type in the brain, where they participate in various homeostatic functions. Transcriptomically diverse astrocyte subpopulations play distinct roles during development and disease progression. However, the biochemical identification of astrocyte subtypes, especially by membrane surface protein glycosylation, remains poorly investigated. Protein tyrosine phosphatase receptor type zeta (PTPRZ) is a highly expressed membrane protein in CNS glia cells that can be modified with diverse glycosylation, including the unique HNK-1 capped O-mannosyl (O-Man) core M2 glycan mediated by brain-specific branching enzyme GnT-IX. Although PTPRZ modified with HNK-1 capped O-Man glycans (HNK-1-O-Man+ PTPRZ) is increased in reactive astrocytes of demyelination model mice, whether such astrocytes emerge in a broad range of disease-associated conditions or are limited to conditions associated with demyelination remains unclear. Here, we show that HNK-1-O-Man+ PTPRZ localizes in hypertrophic astrocytes of damaged brain areas in patients with multiple sclerosis. Furthermore, we show that astrocytes expressing HNK-1-O-Man+ PTPRZ are present in two demyelination mouse models (cuprizone-fed mice and a vanishing white matter disease model), while traumatic brain injury does not induce glycosylation. Administration of cuprizone to Aldh1l1-eGFP and Olig2KICreER/+ ;Rosa26eGFP mice revealed that cells expressing HNK-1-O-Man+ PTPRZ are derived from cells in the astrocyte lineage. Notably, GnT-IX but not PTPRZ mRNA was upregulated in astrocytes isolated from the corpus callosum of cuprizone-model mice. These results suggest that the unique PTPRZ glycosylation plays a key role in the patterning of demyelination-associated astrocytes.

    DOI: 10.1111/jnc.15820

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  • Ddx20, an Olig2 binding factor, governs the survival of neural and oligodendrocyte progenitor cells via proper Mdm2 splicing and p53 suppression. Reviewed International journal

    Norihisa Bizen, Asim K Bepari, Li Zhou, Manabu Abe, Kenji Sakimura, Katsuhiko Ono, Hirohide Takebayashi

    Cell death and differentiation   29 ( 5 )   1028 - 1041   2022.5

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    Olig2 is indispensable for motoneuron and oligodendrocyte fate-specification in the pMN domain of embryonic spinal cords, and also involved in the proliferation and differentiation of several cell types in the nervous system, including neural progenitor cells (NPCs) and oligodendrocytes. However, how Olig2 controls these diverse biological processes remains unclear. Here, we demonstrated that a novel Olig2-binding protein, DEAD-box helicase 20 (Ddx20), is indispensable for the survival of NPCs and oligodendrocyte progenitor cells (OPCs). A central nervous system (CNS)-specific Ddx20 conditional knockout (cKO) demonstrated apoptosis and cell cycle arrest in NPCs and OPCs, through the potentiation of the p53 pathway in DNA damage-dependent and independent manners, including SMN complex disruption and the abnormal splicing of Mdm2 mRNA. Analyzes of Olig2 null NPCs showed that Olig2 contributed to NPC proliferation through Ddx20 protein stabilization. Our findings provide novel mechanisms underlying the Olig2-mediated proliferation of NPCs, via the Ddx20-p53 axis, in the embryonic CNS.

    DOI: 10.1038/s41418-021-00915-8

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  • Ddx20, DEAD box helicase 20, is essential for the differentiation of oligodendrocyte and maintenance of myelin gene expression. Reviewed International journal

    *Anna Simankova, *Norihisa Bizen, Sei Saitoh, Shinsuke Shibata, Nobuhiko Ohno, Manabu Abe, Kenji Sakimura, Hirohide Takebayashi, (*contributed equally)

    Glia   69 ( 11 )   2559 - 2574   2021.7

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    Oligodendrocytes form myelin sheaths that surround axons, contributing to saltatory conduction and proper central nervous system (CNS) function. Oligodendrocyte progenitor cells (OPCs) are generated during the embryonic stage and differentiate into myelinating oligodendrocytes postnatally. Ddx20 is a multifunctional, DEAD-box helicase involved in multiple cellular processes, including transcription, splicing, microRNA biogenesis, and translation. Although defects in each of these processes result in abnormal oligodendrocyte differentiation and myelination, the involvement of Ddx20 in oligodendrocyte terminal differentiation remains unknown. To address this question, we used Mbp-Cre mice to generate Ddx20 conditional knockout (cKO) mice to allow for the deletion of Ddx20 from mature oligodendrocytes. Mbp-Cre;Ddx20 cKO mice demonstrated small body sizes, behavioral abnormalities, muscle weakness, and short lifespans, with mortality by the age of 2 months old. Histological analyses demonstrated significant reductions in the number of mature oligodendrocytes and drastic reductions in the expression levels of myelin-associated mRNAs, such as Mbp and Plp at postnatal day 42. The number of OPCs did not change. A thin myelin layer was observed for large-diameter axons in Ddx20 cKO mice, based on electron microscopic analysis. A bromodeoxyuridine (BrdU) labeling experiment demonstrated that terminal differentiation was perturbed from ages 2 weeks to 7 weeks in the CNS of Mbp-Cre;Ddx20 cKO mice. The activation of mitogen-activated protein (MAP) kinase, which promotes myelination, was downregulated in the Ddx20 cKO mice based on immunohistochemical detection. These results indicate that Ddx20 is an essential factor for terminal differentiation of oligodendrocytes and maintenance of myelin gene expression.

    DOI: 10.1002/glia.24058

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  • Olig2 regulates terminal differentiation and maturation of peripheral olfactory sensory neurons. Reviewed International journal

    Ya-Zhou Wang, Hong Fan, Yu Ji, Kurt Reynolds, Ran Gu, Qini Gan, Takashi Yamagami, Tianyu Zhao, Salaheddin Hamad, Norihisa Bizen, Hirohide Takebayashi, YiPing Chen, Shengxi Wu, David Pleasure, Kit Lam, Chengji J Zhou

    Cellular and molecular life sciences : CMLS   77 ( 18 )   3597 - 3609   2020.9

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    The bHLH transcription factor Olig2 is required for sequential cell fate determination of both motor neurons and oligodendrocytes and for progenitor proliferation in the central nervous system. However, the role of Olig2 in peripheral sensory neurogenesis remains unknown. We report that Olig2 is transiently expressed in the newly differentiated olfactory sensory neurons (OSNs) and is down-regulated in the mature OSNs in mice from early gestation to adulthood. Genetic fate mapping demonstrates that Olig2-expressing cells solely give rise to OSNs in the peripheral olfactory system. Olig2 depletion does not affect the proliferation of peripheral olfactory progenitors and the fate determination of OSNs, sustentacular cells, and the olfactory ensheathing cells. However, the terminal differentiation and maturation of OSNs are compromised in either Olig2 single or Olig1/Olig2 double knockout mice, associated with significantly diminished expression of multiple OSN maturation and odorant signaling genes, including Omp, Gnal, Adcy3, and Olfr15. We further demonstrate that Olig2 binds to the E-box in the Omp promoter region to regulate its expression. Taken together, our results reveal a distinctly novel function of Olig2 in the periphery nervous system to regulate the terminal differentiation and maturation of olfactory sensory neurons.

    DOI: 10.1007/s00018-019-03385-x

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  • Glial pathology in a novel spontaneous mutant mouse of the Eif2b5 gene: a vanishing white matter disease model. Reviewed International journal

    Mika Terumitsu-Tsujita, Hiroki Kitaura, Ikuo Miura, Yuji Kiyama, Fumiko Goto, Yoshiko Muraki, Shiho Ominato, Norikazu Hara, Anna Simankova, Norihisa Bizen, Kazuhiro Kashiwagi, Takuhiro Ito, Yasuko Toyoshima, Akiyoshi Kakita, Toshiya Manabe, Shigeharu Wakana, Hirohide Takebayashi, Hironaka Igarashi

    Journal of neurochemistry   154 ( 1 )   25 - 40   2020.7

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    Vanishing white matter disease (VWM) is an autosomal recessive neurological disorder caused by mutation(s) in any subunit of eukaryotic translation initiation factor 2B (eIF2B), an activator of translation initiation factor eIF2. VWM occurs with mutation of the genes encoding eIF2B subunits (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5). However, little is known regarding the underlying pathogenetic mechanisms or how to treat patients with VWM. Here we describe the identification and detailed analysis of a new spontaneous mutant mouse harboring a point mutation in the Eif2b5 gene (p.Ile98Met). Homozygous Eif2b5I98M mutant mice exhibited a small body, abnormal gait, male and female infertility, epileptic seizures, and a shortened lifespan. Biochemical analyses indicated that the mutant eIF2B protein with the Eif2b5I98M mutation decreased guanine nucleotide exchange activity on eIF2, and the level of the endoplasmic reticulum stress marker activating transcription factor 4 was elevated in the 1-month-old Eif2b5I98M brain. Histological analyses indicated up-regulated glial fibrillary acidic protein immunoreactivity in the astrocytes of the Eif2b5I98M forebrain and translocation of Bergmann glia in the Eif2b5I98M cerebellum, as well as increased mRNA expression of an endoplasmic reticulum stress marker, C/EBP homologous protein. Disruption of myelin and clustering of oligodendrocyte progenitor cells were also indicated in the white matter of the Eif2b5I98M spinal cord at 8 months old. Our data show that Eif2b5I98M mutants are a good model for understanding VWM pathogenesis and therapy development. Cover Image for this issue: doi: 10.1111/jnc.14751.

    DOI: 10.1111/jnc.14887

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  • Diverse dystonin gene mutations cause distinct patterns of Dst isoform deficiency and phenotypic heterogeneity in Dystonia musculorum mice. Reviewed International journal

    Nozomu Yoshioka, Yudai Kabata, Momona Kuriyama, Norihisa Bizen, Li Zhou, Dang M Tran, Masato Yano, Atsushi Yoshiki, Tatsuo Ushiki, Thomas J Sproule, Riichiro Abe, Hirohide Takebayashi

    Disease models & mechanisms   13 ( 5 )   2020.5

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    Loss-of-function mutations in dystonin (DST) can cause hereditary sensory and autonomic neuropathy type 6 (HSAN-VI) or epidermolysis bullosa simplex (EBS). Recently, DST-related diseases were recognized to be more complex than previously thought because a patient exhibited both neurological and skin manifestations, whereas others display only one or the other. A single DST locus produces at least three major DST isoforms: DST-a (neuronal isoform), DST-b (muscular isoform) and DST-e (epithelial isoform). Dystonia musculorum (dt) mice, which have mutations in Dst, were originally identified as spontaneous mutants displaying neurological phenotypes. To reveal the mechanisms underlying the phenotypic heterogeneity of DST-related diseases, we investigated two mutant strains with different mutations: a spontaneous Dst mutant (Dstdt-23Rbrc mice) and a gene-trap mutant (DstGt mice). The Dstdt-23Rbrc allele possesses a nonsense mutation in an exon shared by all Dst isoforms. The DstGt allele is predicted to inactivate Dst-a and Dst-b isoforms but not Dst-e There was a decrease in the levels of Dst-a mRNA in the neural tissue of both Dstdt-23Rbrc and DstGt homozygotes. Loss of sensory and autonomic nerve ends in the skin was observed in both Dstdt-23Rbrc and DstGt mice at postnatal stages. In contrast, Dst-e mRNA expression was reduced in the skin of Dstdt-23Rbrc mice but not in DstGt mice. Expression levels of Dst proteins in neural and cutaneous tissues correlated with Dst mRNAs. Because Dst-e encodes a structural protein in hemidesmosomes (HDs), we performed transmission electron microscopy. Lack of inner plaques and loss of keratin filament invasions underneath the HDs were observed in the basal keratinocytes of Dstdt-23Rbrc mice but not in those of DstGt mice; thus, the distinct phenotype of the skin of Dstdt-23Rbrc mice could be because of failure of Dst-e expression. These results indicate that distinct mutations within the Dst locus can cause different loss-of-function patterns among Dst isoforms, which accounts for the heterogeneous neural and skin phenotypes in dt mice and DST-related diseases.

    DOI: 10.1242/dmm.041608

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  • Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy. Reviewed International journal

    Mikko Muona, Ryosuke Ishimura, Anni Laari, Yoshinobu Ichimura, Tarja Linnankivi, Riikka Keski-Filppula, Riitta Herva, Heikki Rantala, Anders Paetau, Minna Pöyhönen, Miki Obata, Takefumi Uemura, Thomas Karhu, Norihisa Bizen, Hirohide Takebayashi, Shane McKee, Michael J Parker, Nadia Akawi, Jeremy McRae, Matthew E Hurles, Outi Kuismin, Mitja I Kurki, Anna-Kaisa Anttonen, Keiji Tanaka, Aarno Palotie, Satoshi Waguri, Anna-Elina Lehesjoki, Masaaki Komatsu

    American journal of human genetics   99 ( 3 )   683 - 694   2016.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:CELL PRESS  

    The ubiquitin fold modifier 1 (UFM1) cascade is a recently identified evolutionarily conserved ubiquitin-like modification system whose function and link to human disease have remained largely uncharacterized. By using exome sequencing in Finnish individuals with severe epileptic syndromes, we identified pathogenic compound heterozygous variants in UBA5, encoding an activating enzyme for UFM1, in two unrelated families. Two additional individuals with biallelic UBA5 variants were identified from the UK-based Deciphering Developmental Disorders study and one from the Northern Finland Intellectual Disability cohort. The affected individuals (n = 9) presented in early infancy with severe irritability, followed by dystonia and stagnation of development. Furthermore, the majority of individuals display postnatal microcephaly and epilepsy and develop spasticity. The affected individuals were compound heterozygous for a missense substitution, c.1111G>A (p.Ala371Thr; allele frequency of 0.28% in Europeans), and a nonsense variant or c.164G>A that encodes an amino acid substitution p.Arg55His, but also affects splicing by facilitating exon 2 skipping, thus also being in effect a loss-of-function allele. Using an in vitro thioester formation assay and cellular analyses, we show that the p.Ala371Thr variant is hypomorphic with attenuated ability to transfer the activated UFM1 to UFC1. Finally, we show that the CNS-specific knockout of Ufm1 in mice causes neonatal death accompanied by microcephaly and apoptosis in specific neurons, further suggesting that the UFM1 system is essential for CNS development and function. Taken together, our data imply that the combination of a hypomorphic p.Ala371Thr variant in trans with a loss-of-function allele in UBA5 underlies a severe infantile-onset encephalopathy.

    DOI: 10.1016/j.ajhg.2016.06.020

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  • A Synthetic Polymer Scaffold Reveals the Self-Maintenance Strategies of Rat Glioma Stem Cells by Organization of the Advantageous Niche. Reviewed International journal

    Kouichi Tabu, Nozomi Muramatsu, Christian Mangani, Mei Wu, Rong Zhang, Taichi Kimura, Kazuo Terashima, Norihisa Bizen, Ryosuke Kimura, Wenqian Wang, Yoshitaka Murota, Yasuhiro Kokubu, Ikuo Nobuhisa, Tetsushi Kagawa, Issay Kitabayashi, Mark Bradley, Tetsuya Taga

    Stem cells (Dayton, Ohio)   34 ( 5 )   1151 - 62   2016.5

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:WILEY-BLACKWELL  

    Cancer stem cells (CSCs) are believed to be maintained within a microenvironmental niche. Here we used polymer microarrays for the rapid and efficient identification of glioma CSC (GSC) niche mimicries and identified a urethane-based synthetic polymer, upon which two groups of niche components, namely extracellular matrices (ECMs) and iron are revealed. In cultures, side population (SP) cells, defined as GSCs in the rat C6 glioma cell line, are more efficiently sustained in the presence of their differentiated progenies expressing higher levels of ECMs and transferrin, while in xenografts, ECMs are supplied by the vascular endothelial cells (VECs), including SP cell-derived ones with distinctively greater ability to retain xenobiotics than host VECs. Iron is stored in tumor infiltrating host macrophages (Mφs), whose protumoral activity is potently enhanced by SP cell-secreted soluble factor(s). Finally, coexpression of ECM-, iron-, and Mφ-related genes is found to be predictive of glioma patients' outcome. Our polymer-based approach reveals the intrinsic capacities of GSCs, to adapt the environment to organize a self-advantageous microenvironment niche, for their maintenance and expansion, which redefines the current concept of anti-CSC niche therapy and has the potential to accelerate cancer therapy development. Stem Cells 2016;34:1151-1162.

    DOI: 10.1002/stem.2299

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  • Endoplasmic Reticulum-Localized Transmembrane Protein Dpy19L1 Is Required for Neurite Outgrowth. Reviewed International journal

    Keisuke Watanabe, Norihisa Bizen, Noboru Sato, Hirohide Takebayashi

    PloS one   11 ( 12 )   e0167985   2016

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:PUBLIC LIBRARY SCIENCE  

    The endoplasmic reticulum (ER), including the nuclear envelope, is a continuous and intricate membrane-bound organelle responsible for various cellular functions. In neurons, the ER network is found in cell bodies, axons, and dendrites. Recent studies indicate the involvement of the ER network in neuronal development, such as neuronal migration and axonal outgrowth. However, the regulation of neural development by ER-localized proteins is not fully understood. We previously reported that the multi-transmembrane protein Dpy19L1 is required for neuronal migration in the developing mouse cerebral cortex. A Dpy19L family member, Dpy19L2, which is a causative gene for human Globozoospermia, is suggested to act as an anchor of the acrosome to the nuclear envelope. In this study, we found that the patterns of exogenous Dpy19L1 were partially coincident with the ER, including the nuclear envelope in COS-7 cells at the level of the light microscope. The reticular distribution of Dpy19L1 was disrupted by microtubule depolymerization that induces retraction of the ER. Furthermore, Dpy19L1 showed a similar distribution pattern with a ER marker protein in embryonic mouse cortical neurons. Finally, we showed that Dpy19L1 knockdown mediated by siRNA resulted in decreased neurite outgrowth in cultured neurons. These results indicate that transmembrane protein Dpy19L1 is localized to the ER membrane and regulates neurite extension during development.

    DOI: 10.1371/journal.pone.0167985

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  • A growth-promoting signaling component cyclin D1 in neural stem cells has antiastrogliogenic function to execute self-renewal. Reviewed International journal

    Norihisa Bizen, Toshihiro Inoue, Takeshi Shimizu, Kouichi Tabu, Tetsushi Kagawa, Tetsuya Taga

    Stem cells (Dayton, Ohio)   32 ( 6 )   1602 - 15   2014.6

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:WILEY-BLACKWELL  

    Self-renewing proliferation of neural stem cells (NSCs) is intimately linked to the inhibition of neuronal and glial differentiation, however, their molecular linkage has been poorly understood. We have proposed a model previously explaining partly this linkage, in which fibroblast growth factor 2 (FGF2) and Wnt signals cooperate to promote NSC self-renewal via β-catenin accumulation, which leads to the promotion of proliferation by lymphoid enhancer factor (LEF)/T-cell factor (TCF)-mediated cyclin D1 expression and at the same time to the inhibition of neuronal differentiation by β-catenin-mediated potentiation of Notch signaling. To fully understand the mechanisms underlying NSC self-renewal, it needs to be clarified how these growth factor signals inhibit glial differentiation as well. Here, we demonstrate that cyclin D1, a NSC growth promoting signaling component and also a common component of FGF2 and Wnt signaling pathways, inhibits astroglial differentiation of NSCs. Interestingly, this effect of cyclin D1 is mediated even though its cell cycle progression activity is blocked. Forced downregulation of cyclin D1 enhances astrogliogenesis of NSCs in culture and in vivo. We further demonstrate that cyclin D1 binds to STAT3, a transcription factor downstream of astrogliogenic cytokines, and suppresses its transcriptional activity on the glial fibrillary acidic protein (Gfap) gene. Taken together with our previous finding, we provide a novel molecular mechanism for NSC self-renewal in which growth promoting signaling components activated by FGF2 and Wnts inhibit neuronal and glial differentiation.

    DOI: 10.1002/stem.1613

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  • [Roles of GSK3beta signaling in the self-renewal of neural progenitor cells].

    Tetsushi Kagawa, Norihisa Bizen, Norihisa Bizen, Tetsuya Taga

    Seikagaku. The Journal of Japanese Biochemical Society   86 ( 1 )   68 - 71   2014.2

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  • Gene Regulation of Prominin-1 (CD133) in Normal and Cancerous Tissues. Reviewed International journal

    Kouichi Tabu, Norihisa Bizen, Tetsuya Taga, Shinya Tanaka

    Advances in experimental medicine and biology   777   73 - 85   2013

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:SPRINGER  

    A pentaspan membrane glycoprotein prominin-1 (frequently called CD133 in human) is widely used as a surface marker to identify and isolate normal stem/progenitor cells from various organs, although it is also expressed in some types of differentiated cells. Since CD133 was identified as a universal marker to isolate cancer stem cells (CSCs) in tumors derived from multiple tissues, much attention has been directed toward the relationship between its gene regulation and identity of CSCs (i.e., cancer stemness). Prominin-1 (PROM1) gene possesses five alternative promoters yielding multiple first exons within the 5'-untranslated region (UTR) and also splicing variants affecting the open reading frame (ORF) sequence, implicating the complicated gene regulation in a context-dependent manner. This chapter aims to organize the accumulated findings on prominin-1 with a focus on its altered expression and regulation in normal and cancerous cells and to discuss potential regulatory networks underlying cancer stemness.

    DOI: 10.1007/978-1-4614-5894-4_5

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  • Analysis of an alternative human CD133 promoter reveals the implication of Ras/ERK pathway in tumor stem-like hallmarks. Reviewed International journal

    Kouichi Tabu, Taichi Kimura, Ken Sasai, Lei Wang, Norihisa Bizen, Hiroshi Nishihara, Tetsuya Taga, Shinya Tanaka

    Molecular cancer   9 ( 39 )   39 - 39   2010.2

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:BIOMED CENTRAL LTD  

    BACKGROUND: An increasing number of studies support the presence of stem-like cells in human malignancies. These cells are primarily responsible for tumor initiation and thus considered as a potential target to eradicate tumors. CD133 has been identified as an important cell surface marker to enrich the stem-like population in various human tumors. To reveal the molecular machinery underlying the stem-like features in tumor cells, we analyzed a promoter of CD133 gene using human colon carcinoma Caco-2 and synovial sarcoma Fuji cells, which endogenously express CD133 gene. RESULTS: A reporter analysis revealed that P5 promoter, located far upstream in a human CD133 gene locus, exhibits the highest activity among the five putative promoters (P1 to P5). Deletion and mutation analysis identified two ETS binding sites in the P5 region as being essential for its promoter activity. Electrophoretic mobility shift assays demonstrated the specific binding between nuclear factors and the ETS binding sequence. Overexpression of dominant-negative forms of Ets2 and Elk1 resulted in the significant decrease of P5 activity. Furthermore, treatment of Fuji cells with a specific MEK/ERK inhibitor, U0126, also markedly decreased CD133 expression, but there was no significant effect in Caco-2 cells, suggesting cell type-specific regulation of CD133 expression. Instead, the side population, another hallmark of TSLCs, was dramatically diminished in Caco-2 cells by U0126. Finally, Ras-mediated oncogenic transformation in normal human astrocytes conferred the stem-like capability to form neurosphere-like colonies with the increase of CD133 mRNA expression. CONCLUSIONS: In conclusion, the Ras/ERK pathway at least in part contributes to the maintenance and the acquisition of stem-like hallmarks, although the extent of its contribution is varied in a cell type-specific manner. These findings could help our comprehensive understanding of tumor stemness, and also improve the development of eradicative therapies against human malignancies.

    DOI: 10.1186/1476-4598-9-39

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Books

  • 神経幹細胞の分化制御機構:細胞外来生シグナルと細胞内在性プログラムによる分化制御

    備前典久, 鹿川哲史, 田賀哲也( Role: Contributor ,  再生医療シリーズ 脳神経系の発生・再生の融合的新展開 28-33ページ)

    診断と治療社  2015.1 

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  • GSK3bシグナル経路による神経前駆細胞の自己複製制御

    鹿川哲史, 備前典久, 清水健史, 田賀哲也( Role: Contributor ,  生化学 第86巻第1号 68-71ページ)

    日本生化学会  2014 

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  • LIF (Leukemia Inhibitory Factor)

    備前典久, 田賀哲也( Role: Contributor ,  臨床免疫・アレルギー科 増刊 「サイトカインのすべて」Vol.57 545-552ページ)

    科学評論社  2012 

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  • アストロサイトの発生・分化

    鹿川哲史, 備前典久, 田賀哲也( Role: Contributor ,  Clinical Neuroscience 別冊, Vol 29, No.11, Page 1239-1242)

    中外医学社  2011 

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  • 第2章 細胞 (その他の幹細胞など)-ものづくりから考察する幹細胞の居心地-

    田賀哲也, 椨康一, 備前典久( Role: Contributor ,  ものづくり技術からみる再生医療-細胞研究・創薬・治療- Page 18-24)

    シーエムシー出版  2011 

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MISC

  • RNA代謝調節因子Ddx20による神経前駆細胞およびオリゴデンドロサイト前駆細胞維持機構

    備前典久, 竹林浩秀

    神経化学トピックス   2022.1

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  • 神経幹/前駆細胞における細胞周期調節因子cyclin D1は細胞周期非依存的にアストロサイト分化を阻害する(Cyclin D1 inhibits astrocyte differentiation from neural stem/progenitor cells in a manner independent of cell cycle progression)

    備前 典久, 井上 俊洋, 清水 健史, 鹿川 哲史, 田賀 哲也

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   83回・33回   3P - 0876   2010.12

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    Language:English   Publisher:(公社)日本生化学会  

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  • 神経幹細胞/前駆細胞における細胞周期調節因子cyclin D1のアストロサイト分化抑制機構(Molecular mechanism underlying cyclin D1 mediated inhibition of astrocyte differentiation from neural stem/progenitor cells)

    備前 典久, 井上 俊洋, 清水 健史, 鹿川 哲史, 田賀 哲也

    神経化学   49 ( 2-3 )   536 - 536   2010.8

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  • サイクリンD1は神経幹細胞/前駆細胞からの星状細胞分化を細胞周期調節非依存性に抑制する(Cyclin D1 inhibits astrocyte differentiation from neural stem/progenitor cells in a manner independent of cell cycle regulation)

    備前 典久, 井上 俊洋, 清水 健史, 鹿川 哲史, 田賀 哲也

    神経化学   48 ( 2-3 )   205 - 205   2009.6

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  • 神経幹細胞画分における細胞周期調節因子cyclin D1はアストロサイト分化を阻害する(Cyclin D1 inhibits astrocyte differentiation in the section of neural stem cell)

    備前 典久, 井上 俊洋, 清水 健史, 鹿川 哲史, 田賀 哲也

    神経化学   47 ( 2-3 )   245 - 245   2008.8

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Awards

  • 令和4年度 新潟大学 優秀論文表彰

    2022.11  

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  • 第9回 学長賞 (若手教員研究奨励)

    2022.9   新潟大学  

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  • 大会長賞

    2021.9   第109回日本解剖学会関東支部学術集会  

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  • 若手優秀発表賞

    2017.12   次世代脳プロジェクト・冬のシンポジウム   Identification of a novel Olig2-binding factor indispensable for oligodendrogenesis in central nervous system

    備前 典久

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  • 優秀論文賞

    2014.3   東京医科歯科大学 難治疾患研究所   A growth-promoting signaling component cyclin D1 in neural stem cells has anti-astrogliogenic function to execute self-renewal. Stem Cells, 32:1602-1615, 2014

    備前 典久

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Research Projects

  • オリゴデンドロサイト由来脂質メディエーターによる脳内ホメオスタシス維持機構の解明

    2022.9 - 2025.5

    System name:医学系研究助成

    Awarding organization:武田科学振興財団

    備前典久

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  • 胎生期神経幹細胞における転写-RNA代謝制御機構に立脚した中枢神経系奇形の病態解明

    2022.4 - 2024.3

    Awarding organization:公益財団法人 日本二分脊椎・水頭症研究振興財団 研究助成

    備前典久

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  • RNAヘリカーゼDdx20変異マウスにおける運動ニューロン変性機構の解明とALS病態との共通メカニズムの探索

    2022.4 - 2023.3

    System name:公益信託宮田幸比古記念ALS研究助成基金

    備前典久

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  • オリゴデンドロサイトによる脳内ホメオスタシス制御機構の解明

    2022.2 - 2022.12

    System name:LEGEND Research Grant Program 2021(後期)

    備前典久

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  • オリゴデンドロサイト機能異常が惹起するp53誘導性神経変性機構の分子基盤解明

    Grant number:20K07241

    2020.4 - 2023.3

    System name:科学研究費助成事業 基盤研究(C)

    Research category:基盤研究(C)

    Awarding organization:日本学術振興会

    備前 典久

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    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

    本研究では、RNAヘリカーゼObp2の成熟オリゴデンドロサイト(OL)特異的欠損マウス(Mbp-Cre;Obp2 cKOマウス)の解析で我々が見出した、明確なOL分化異常を伴わずにニューロン内のp53経路活性化および神経変性を引き起こすメカニズムの解明を通して、OL-ニューロン相互作用のさらなる理解を目指す。
    今年度は、前年度行ったRNA-seqの結果をもとに、さらなるOLとニューロン双方の表現型解析を行った。ニューロンにおいてはシナプス関連遺伝子群の発現低下および神経活動マーカーのc-fosやArcの発現低下が認められた。一方、オリゴデンドロサイトではDNA損傷の蓄積やp21の発現亢進が認められたほか、コレステロール合成関連遺伝子や脂質メディエーター関連遺伝子の発現低下が生じていた。RNA-seqの解析から、DNA修復関連遺伝子のスプライシング異常が多数検出され、DNA修復機構の破綻がDNA損傷蓄積の原因の1つである可能性が考えられた。さらに興味深いことに、Obp2欠損OLで顕著に減少する脂質メディエーター関連分子の発現を制御するシグナルのエフェクター分子と、Obp2が相互作用することを免疫沈降で確認した。これらの結果は、Obp2欠損OLではOL関連遺伝子発現の低下に先駆けて、ゲノムの不安定化や代謝異常が生じており、これがニューロン内のp53の蓄積や神経変性の要因となる可能性が示唆している。

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  • Elucidation of the molecular mechanisms underlying the coupling between transcription and RNA metabolism during myelination

    Grant number:17K15542

    2017.4 - 2020.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Young Scientists (B)

    Awarding organization:Japan Society for the Promotion of Science

    Bizen Norihisa

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\4160000 ( Direct Cost: \3200000 、 Indirect Cost:\960000 )

    Oligodendrocytes (OLs) form the myelin sheaths around axons and regulate the axonal conduction in central nervous system (CNS). We have identified a novel Olig2-binding factor Obp2, which is involved in the transcription regulation and RNA metabolism. To elucidate the role of Obp2 in the myelination, we generated mature OL-specific Obp2 deficient mice (Mbp2-cre: Obp2 cKO). OL differentiation and myelinization are significantly suppressed in the spinal cords of Obp2-deficient mice. RNA-seq detected the abnormal splicing of OL-related factors. In addition, we found that the expression of snRNAs, which are main components of spliceosome, was significantly suppressed in Obp2-deficient spinal cord. Furthermore, the C-terminal region of Obp2, which binds to Olig2, promoted the activation of OL-related gene promoters. Thus, these results suggest that Obp2 is a key regulator for OL differentiation and myelination through RNA splicing and transcriptional regulation.

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  • 小脳失調症状を呈するRNA代謝-ミエリン形成異常マウスの解析

    2017 - 2018

    System name:平成29年度 塚田医学奨学助成金

    Awarding organization:塚田医学奨学基金

    備前 典久

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    Authorship:Principal investigator  Grant type:Competitive

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  • Regulation of inflammation in brain induced by glial cell death.

    Grant number:16K15168

    2016.4 - 2019.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Challenging Exploratory Research

    Awarding organization:Japan Society for the Promotion of Science

    Takebayashi Hirohide, Horie Masao, Hossain MD Ibrahim, Bizen Norihisa, Simankova Anna, Zhou Lei, Mori Yukiko

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    Grant amount:\3640000 ( Direct Cost: \2800000 、 Indirect Cost:\840000 )

    In this study, we backcrossed jimpy mutant mice to C57BL/6 mice to generate B6:jimpy mouse. In addition, we established immunohistochemical staining to detect immune cells and in situ probes of various cytokines. Using these staining methods, we can detect brain inflammation on tissue sections. We also crossed jimpy mice with a mutant mice of translation initiation factor, and then, confirmed more severe phenotype than single mutant mice. Finally, we demonstrated a novel oligodendrocyte pathology in dystonia musculorum mice, in which proliferation of oligodendrocyte progenitor cells are reduced at 3 weeks old.

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  • Elucidation of molecular mechanisms underlying a novel Olig2 binding factor-mediated oligodendrocyte differentiation

    Grant number:15K18373

    2015.4 - 2018.3

    System name:Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)

    Research category:Grant-in-Aid for Young Scientists (B)

    Awarding organization:Japan Society for the Promotion of Science

    Bizen Norihisa

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    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

    We identified a novel Olig2 binding factor, Obp2 and analyzed central nervous system-specific Obp2 mutant mice. These mice exhibited severe loss of oligodendrocyte differentiation without motor neuron defects.We further found that Obp2 contributed to the maintenance of Olig2-positive neural precursor cells and oligodendrocyte progenitor cells through the regulation of DNA damage-p53 axis in central nervous system.
    We also demonstrated that OIF, which is a truncated form of Obp2 strongly induced the transcriptional activity of oligodendrocyte related genes such as PLP and MBP, and promoted oligodendrocyte differentiation in dysmyelinating mice.
    In conclusion, we suggest that Obp2 is indispensable for oligodendrocyte development and OIF could be useful for the therapy of demyelinating diseases.

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  • Analysis on neuronal circuits responsible for involuntary movements

    Grant number:15H04667

    2015.4 - 2018.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (B)

    Awarding organization:Japan Society for the Promotion of Science

    Takebayashi Hirohide, NAMBU ATSUSHI, CHIKEN SATOMI, SANO HIROMI, HORIE MASAO, BIZEN NORIHISA, HOSSAIN MD IBRAHIM, MORI YUKIKO

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    Grant amount:\17550000 ( Direct Cost: \13500000 、 Indirect Cost:\4050000 )

    Dystonia musculorum (dt) mice have a loss-of-function mutation in the Dystonin (Dst) gene, which encodes a cytoskeleton regulator. Dt mice show movement disorders, such as cerebellar ataxia and dystonia, as well as sensory neuropathy. Since dt mice die around four weeks old, we investigated why they show growth retardation and die at premature stage. We observed neuronal cell death in the trigeminal motor nucleus (Mo5 nucleus). We also report atrophy and weak contraction of the masseter muscles in dt mice by histological analyses and electromyographic recording, which are innervated by Mo5 motoneurons. Taken together, our findings strongly suggest that mastication in dt mice is affected due to abnormalities of Mo5 motoneurons and masseter muscles, which is one possible reason of growth retardation at the post-weaning stages. In addition, we observed reduced proliferation of oligodendrocyte progenitor cells in the brain of dt mice.

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  • 人工幹細胞ニッチを用いた神経幹細胞の未分化性維持 と分化を制御する分子基盤解明

    2012 - 2013

    System name:難治疾患研究所研究助成

    Awarding organization:東京医科歯科大学 難治疾患研究所

    備前 典久

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    Authorship:Principal investigator  Grant type:Competitive

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