論文 - 岡野　栄之

Visualization, direct isolation, and transplantation of midbrain dopaminergic neurons

Sawamoto Kazunobu, Nakao Naoyuki, Kobayashi Kazuto, Matsushita Natsuki, Takahashi Hiroshi, Kakishita Koji, Yamamoto Atsuyo, Yoshizaki Takahito, Terashima Toshio, Murakami Fujio, Itakura Toru, Okano Hideyuki

Proceedings of National Academy of Sciences of the United States of America 98 （ 11 ） 6423-6428 2001年05月

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Expression of mouse igf2 mRNA-binding protein 3 and its implications for the developing central nervous system

Mori Hiroshi, Sakakibara Shin-ichi, Imai Takao, Nakamura Yuki, Iijima Takatoshi, Suzuki Akira, Yuasa Yoshihiro, Takeda Masatoshi, Okano Hideyuki

Journal of Neuroscience Research 64 （ 2 ） 132-143 2001年04月

研究論文（学術雑誌）, 共著

Expression of the neural RNA-binding protein Musashi1 in human gliomas

Toda M, Iizuka Y, Yu W, Imai T, Ikeda E, Yoshida K, Kawase T, Kawakami Y, Okano H, Uyemura K

Glia 34 （ 1 ） 1-7 2001年04月

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ES細胞を用いた再生医療への戦略

岸憲幸，岡野栄之

産婦人科の世界 53 （ 増刊号 ） 264-269 2001年04月

研究論文（学術雑誌）, 共著

神経幹細胞と臨床応用

森裕，武田雅俊，岡野栄之

Dementia Japan 15 （ 1 ） 68-74 2001年04月

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Murine homologs of deltex define a novel gene family involved in vertebrate Notch signaling and neurogenesis

Kishi Noriyuki, Tang Zhenyu, Maeda Yusuke, Hirai Asami, Mo Rong, Ito Mikiko, Suzuki Satoshi, Nakao Keiko, Kinoshita Tsutomu, Kadesch Tom, Hui Chi Chung, Artavanis-Tsakonas Spyros, Okano Hideyuki, Matsuno Kenji

International Journal of Developmental Neuroscience 19 （ 1 ） 21 - 35 2001年02月

ISSN  0736-5748

　概要を見る

<p>Notch signaling plays an important role in cell-fate specification in multicellular organisms by regulating cell-cell communication. The Drosophila deltex gene encodes a modulator of the Notch pathway that has been shown to interact physically with the Ankyrin repeats of Notch. We isolated four distinct cDNAs corresponding to mouse homologs of deltex - mouse Deltex1 (MDTX1), mouse Deltex2 (MDTX2), mouse Deltex2ΔE (MDTX2ΔE), and mouse Deltex3 (MDTX3). Deduced amino acid sequences of these four cDNAs showed a high degree of similarity to Drosophila Deltex and its human homolog, DTX1 throughout their lengths, even though they possess distinct structural features. MDTX proteins formed homotypic and heterotypic multimers. We found that these genes were expressed in the central, peripheral nervous system and in the thymus, overlapping with those of mouse Notch1. In mammalian tissue culture cells, overexpression of any of the four mouse deltex homologs suppressed the transcriptional activity of E47, a basic helix-loop-helix (bHLH) protein, in a manner similar to suppression by an activated form of human Notch1 or human DTX1. In addition, overexpression of MDTX2 and MDTX2ΔE in C2C12 cells under differentiation-inducing conditions suppressed the expression of myogenin, one of the myogenic transcriptional factors; this was also similar to a previously reported activity of constitutively activated Notch. Furthermore, misexpression of any of the MDTX genes in Xenopus embryos resulted in an expansion of the region expressing the neural cell adhesion molecule (N-CAM) gene, a marker for the neuroepithelium. Collectively, our results suggest that these mouse deltex homologs are involved in vertebrate Notch signaling and regulation of neurogenesis. Copyright © 2001 Elsevier Science Ltd.</p>

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Caspase-11 mediates oligodendrocyte cell death and pathogenesis of autoimmune-mediated demyelination

Hisahara S., Yuan J., Momoi T., Okano H., Miura M.

Journal of Experimental Medicine 193 （ 1 ） 111 - 122 2001年01月

ISSN  0022-1007

　概要を見る

<p>Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory diseases of the central nervous system (CNS) characterized by localized areas of demyelination. The mechanisms underlying oligodendrocyte (OLG) injury in MS and EAE remain unknown. Here we show that caspase-11 plays crucial roles in OLG death and pathogenesis in EAE. Caspase-11 and activated caspase-3 were both expressed in OLGs in spinal cord EAE lesions. OLGs from caspase-11-deficient mice were highly resistant to the cell death induced by cytotoxic cytokines. EAE susceptibility and cytokine concentrations in the CNS were significantly reduced in caspase-11-deficient mice. Our findings suggest that OLG death is mediated by a pathway that involves caspases-11 and -3 and leads to the demyelination observed in EAE.</p>

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Nestin-EGFP transgenic mice

Kawaguchi Ayano, Miyata Takaki, Sawamoto Kazunobu, Takashita Noriko, Murayama Ayako, Akamatsu Wado, Ogawa Masaharu, Okabe Masaru, Tano Yasuo, Goldman Steven A., Okano Hideyuki

Molecular and Cellular Neuroscience 17 （ 2 ） 259 - 273 2001年

ISSN  1044-7431

　概要を見る

<p>We generated transgenic mice carrying enhanced green fluorescent protein (EGFP) under the control of the nestin second-intronic enhancer (E/nestin:EGFP). Flow cytometry followed by in vitro assays revealed that in situ EGFP expression in the embryonic brain correlated with the mitotic index, the cogeneration of both neurons and gila, and the frequency of neurosphere formation in vitro. High-level EGFP expressors derived from embryos included a distinct subpopulation of cells that were self-renewable and multipotent, criteria that define neural stern cells (NSCs). Such cells were largely absent among lower-level or non-EGFP expressors, thereby permitting us to enrich for NSCs using EGFP expression level. In adults, although E/nestin:EGFP-positive cells included the NSC population, the frequency of neurosphere formation did not correlate directly with the level of EGFP expression. However, moderately EGFP-expressing cells in adults gained EGFP intensity when they formed neurospheres, suggesting embryonic and adult NSCs exist in different microenvironments in vivo.</p>

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Neural stem cell, as a source of graft material for transplantation in neuronal disease

Akamatsu W., Okano H.

No To Hattatsu 33 （ 2 ） 114 - 120 2001年

ISSN  0029-0831

　概要を見る

<p>Self-renewing and multipotent neural stem cells are present in the adult human brain. We successfully harvested neural stem cells from mice and humans using misexpressed EGFP proteins under the control of the nestin second intron enhancer. High-level EGFP expressors derived from mouse embryos included a distinct subpopulation of cells that were self-renewable and multipotent. Further, we obtained that neural progenitor cells from rat fetal spinal cords using a neurosphere technique, and demonstrated their ability to divide and differentiate into neurons in vivo, where they were integrated into the host tissue in the injured rat spinal cord with resultant behavioral improvement of the recipient rat. We also harvested tyrosine hydroxylase-positive neurons from a transgenic mouse expressing GFP under the control of the tyrosine hydroxylase promoter, and successfully transplanted them into the striatum of rats with parkinsonism with marked improvement of the neurological symptoms. Since neural stem cells can adapt well in the host CNS, studies should focus on their application as a vector in gene therapy and on the introduction in vivo or ex vivo of genes to control their proliferation and differentiation. Neural stem cells are a potential, useful source for developing new therapy for CNS disorders.</p>

Critical role of Caenorhabditis elegans homologs of Cds1 (Chk2)-related kinases in meiotic recombination

Oishi I., Iwai K., Kagohashi Y., Fujimoto H., Kariya K. I., Kataoka T., Sawa H., Okano H., Otani H., Yamamura H., Minami Y.

Molecular and Cellular Biology 21 （ 4 ） 1329 - 1335 2001年

ISSN  0270-7306

　概要を見る

<p>Although chromosomal segregation at meiosis I is the critical process for genetic reassortment and inheritance, little is known about molecules involved in this process in metazoa. Here we show by utilizing double-stranded RNA (dsRNA)-mediated genetic interference that novel protein kinases (Ce-CDS-1 and Ce-CDS-2) related to Cds1 (Chk2) play an essential role in meiotic recombination in Caenorhabditis elegans. Injection of dsRNA into adult animals resulted in the inhibition of meiotic crossing over and induced the loss of chiasmata at diakenesis in oocytes of F₁ animals. However, electron microscopic analysis revealed that synaptonemal complex formation in pachytene nuclei of the same progeny of injected animals appeared to be normal. Thus, Ce-CDS-1 and Ce-CDS-2 are the first example of Cds1-related kinases that are required for meiotic recombination in multicellular organisms.</p>

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tincar encodes a novel transmembrane protein expressed in the Tinman-expressing cardioblasts of Drosophila

岡野 栄之

MECHANISMS OF DEVELOPMENT 119   S279 - S283 2002年12月

研究論文（学術雑誌）,  ISSN  0925-4773

中枢神経系の再生医療

金子慎二郎，岩波明生，中村雅也，小川祐人，戸山芳昭，岡野栄之

日本小児科学会雑誌 106 （ 12 ） 1736-1743 2002年12月

研究論文（学術雑誌）, 共著

教育研修講座―神経幹細胞と損傷脊髄の再生

岩波明生，中村雅也，小川祐人，金子慎二郎，戸山芳昭，岡野栄之

日本整形外科学会誌 76 （ 12 ） 579-591 2002年12月

研究論文（学術雑誌）, 共著

小児科領域における最先端医療＜再生医療の最近の進歩＞―中枢神経系の再生医療

金子慎二郎，岩波明生，中村雅也，小川祐人，戸山芳昭，岡野栄之

日本小児科学会雑誌 106 （ 12 ） 1736-1743 2002年12月

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神経幹細胞の分化制御

岡田誠司，岡野栄之

Brain medical 14 （ 4 ） 14-21 2002年12月

研究論文（学術雑誌）, 共著

光る脳みそ

村山綾子，岡野栄之

細胞工学 21 （ 12 ） 1405-1405 2002年12月

研究論文（学術雑誌）, 共著

ヒト神経幹細胞移植

島崎琢也，岡野栄之

神経研究の進歩 46 （ 6 ） 790-797 2002年12月

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tincar encodes a novel transmembrane protein expressed in the Tinman-expressing cardioblasts of Drosophila

Hirota Yuki, Sawamoto Kazunobu, Okano Hideyuki

Gene expression patterns 2 （ 3-4 ） 323-327 2002年12月

研究論文（学術雑誌）, 共著

神経幹細胞と損傷脊髄の再生

岩波明生，小川祐人，中村雅也，金子慎二郎，戸山芳昭，岡野栄之

日本整形外科学会雑誌 76 （ 12 ） 579-589 2002年12月

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RNA-binding protein Musashi family

Sakakibara Shin ichi, Nakamura Yuki, Yoshida Tetsu, Shibata Shinsuke, Koike Masato, Takano Hiroshi, Ueda Shuichi, Uchiyama Yasuo, Noda Tetsuo, Okano Hideyuki

Proceedings of the National Academy of Sciences of the United States of America 99 （ 23 ） 15194 - 15199 2002年11月

ISSN  0027-8424

　概要を見る

<p>Homologues of the Musashi family of RNA-binding proteins are evolutionarily conserved across species. In mammals, two members of this family, Musashil (Msil) and Musashi2 (Msi2), are strongly coexpressed in neural precursor cells, including CNS stem cells. To address the in vivo roles of msi in neural development, we generated mice with a targeted disruption of the gene encoding Msil. Homozygous newborn mice frequently developed obstructive hydrocephalus with aberrant proliferation of ependymal cells in a restricted area surrounding the Sylvius aqueduct. These observations indicate a vital role for msil in the normal development of this subpopulation of ependymal cells, which has been speculated to be a source of postnatal CNS stem cells. On the other hand, histological examination and an in vitro neurosphere assay showed that neither the embryonic CNS development nor the self-renewal activity of CNS stem cells in embryonic forebrains appeared to be affected by the disruption of msil, but the diversity of the cell types produced by the stem cells was moderately reduced by the msil deficiency. Therefore, we performed antisense ablation experiments to target both msi1 and msi2 in embryonic neural precursor cells. Administration of the antisense peptidenucleotides, which were designed to specifically down-regulate msi2 expression, to msi1^-/- CNS stem cell cultures drastically suppressed the formation of neurospheres in a dose-dependent manner. Antisense-treated msi1^-/- CNS stem cells showed a reduced proliferative activity. These data suggest that msi1 and msi2 are cooperatively involved in the proliferation and maintenance of CNS stem cell populations.</p>

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