研究者詳細 - 岡野　栄之

論文 - 岡野　栄之

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神経形成における幹細胞と移植

岩本範顕，小川祐人，戸山芳昭，岡野栄之

今日の移植 13 （ 4 ） 343-348 2000年07月

研究論文（学術雑誌）, 共著

Nerve growth factor protects oligodendrocytes from tumor necrosis factor-α-induced injury through Akt-mediated signaling mechanisms

Takano Riya, Hisahara Shin, Namikawa Kazuhiko, Kiyama Hiroshi, Okano Hideyuki, Miurat Masayuki

Journal of Biological Chemistry 275 （ 21 ） 16360 - 16365 2000年05月

ISSN 0021-9258

Tumor necrosis factor-α is thought to be one of the most important inflammatory cytokines associated with the demyelinating disease multiple sclerosis. We determined whether neurotrophins could protect oligodendrocytes from tumor necrosis factor-α-mediated cytotoxicity. Among the neurotrophins tested, nerve growth factor was most effective at preventing cell death. Nerve growth factor also prevented the tumor necrosis factor-induced loss of mitochondrial membrane potential. Overexpression of constitutively active Akt, a downstream target of phosphatidylinositol 3-kinase, but not of constitutively active MEK, protected oligodendrocytes from tumor necrosis factor-induced injury. Moreover, overexpression of dominant-negative Akt negated the protective effects of nerve growth factor on tumor necrosis factor-mediated oligodendrocyte cytotoxicity. These findings indicate that the Akt pathway is crucial in nerve growth factor-mediated oligodendrocyte protection.

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Conditional expression of anti-apoptotic protein p35 by Cre-mediated DNA recombination in cardiomyocytes from loxP-p35-transgenic mice

Araki Takashi, Shibata Mamoru, Takano Riya, Hisahara Shin, Imamura Si, Fukuuchi Yasuo, Saruta Takao, Okano Hideyuki, Miura Masayuki

Cell Death and Differntiation 7 （ 5 ） 485-492 2000年05月

研究論文（学術雑誌）, 共著

Mutations modulating the Argos-regulated signaling pathway in Drosophila eye development

Taguchi Akiko, Sawamoto Kazunobu, Okano Hideyuki

Genetics 154 （ 4 ） 1639 - 1648 2000年04月

ISSN 0016-6731

Argos is a secreted protein that contains an EGF-like domain and acts as an inhibitor of Drosophila EGF receptor activation. To identify genes that function in the Argos-regulated signaling pathway, we performed a genetic screen for enhancers and suppressors of the eye phenotype caused by the overexpression of argos. As a result, new alleles of known genes encoding components of the EGF receptor pathway, such as Star, sprouty, bulge, and clown, were isolated. To study the role of clown in development, we examined the eye and wing phenotypes of the clown mutants in detail. In the eye discs of clown mutants, the pattern of neuronal differentiation was impaired, showing a phenotype similar to those caused by a gain-of-function EGF receptor mutation and overexpression of secreted Spitz, an activating ligand for the EGF receptor. There was also an increased number of pigment cells in the clown eyes. Epistatic analysis placed clown between argos and Ras1. In addition, we found that clown negatively regulated the development of wing veins. These results suggest that the clown gene product is important for the Argos-mediated inhibition of EGF receptor activation during the development of various tissues. In addition to the known genes, we identified six mutations of novel genes. Genetic characterization of these mutants suggested that they have distinct roles in cell differentiation and/or survival regulated by the EGF receptor pathway.

外傷性脊髄損傷に対する神経幹細胞移植の試み

小川祐人，宮田卓樹，澤本和延，渡辺雅彦，戸山芳昭，岡野栄之

日本パラプレジア医学会雑誌 13 （ 1 ） 144-145 2000年04月

研究論文（学術雑誌）, 共著

The interaction between the Drosophila secreted protein Argos and the epidermal growth factor receptor inhibits dimerization of the receptor and binding of secreted spitz to the receptor

Jin Ming Hao, Sawamoto Kazunobu, Ito Mikiko, Okano Hideyuki

Molecular and Cellular Biology 20 （ 6 ） 2098 - 2107 2000年03月

ISSN 0270-7306

Drosophila Argos (Aos), a secreted protein with an epidermal growth factor (EGF)-like domain, has been shown to inhibit the activation of the Drosophila EGF receptor (DER). However, it has not been determined whether Aos binds directly to DER or whether regulation of the DER activation occurs through some other mechanism. Using DER-expressing cells (DER/S2) and a recombinant DER extracellular domain-Fc fusion protein (DER-Fc), we have shown that Aos binds directly to the extracellular domain of DER with its carboxyl-terminal region, including the EGF-like domain. Furthermore, Aos can block the binding of secreted Spitz (sSpi), a transforming growth factor α- like ligand of DER, to the extracellular domain of DER. We observed that sSpi stimulates the dimerization of both the soluble DER extracellular domain (sDER) and the intact DER in the DER/S2 cells and that Aos can block the sSpi-induced dimerization of both sDER and intact DER. Moreover, we have shown that, by directly interacting with DER, Aos and SpiAos (a chimeric protein that is composed of the N-terminal region of Spi and the C-terminal region of Aos) inhibit the dimerization and phosphorylation of DER that are induced by DER's overexpression in the absence of sSpi. These results indicate that Aos exerts its inhibitory function through dual molecular mechanisms: by blocking both the receptor dimerization and the binding of activating ligand to the receptor. This is the first description of this novel inhibitory mechanism for receptor tyrosine kinases.

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In vitro neurogenesis by progenitor cells isolated from the adult human hippocampus

Roy Neeta Singh, Wang Su, Jiang Li, Kang Jian, Benraiss Abdellatif, Harrison-Restelli Catherine, Fraser Richard A R, Couldwell William T., Kawaguchi Ayano, Okano Hideyuki, Nedergaard Maiken, Goldman Steven A.

Nature Medicine 6 （ 3 ） 271 - 277 2000年03月

ISSN 1078-8956

Neurogenesis persists in the adult mammalian hippocampus. To identify and isolate neuronal progenitor cells of the adult human hippocampus, we transfected ventricular zone-free dissociates of surgically-excised dentate gyrus with DNA encoding humanized green fluorescent protein (hGFP), placed under the control of either the nestin enhancer (E/nestin) or the Tα1 tubulin promoter (P/Tα1), two regulatory regions that direct transcription in neural progenitor cells. The resultant P/Tα1:hGFP⁺, and E/nestin:enhanced (E)GFP⁺ cells expressed βIII-tubulin or microtubule- associated protein-2; many incorporated bromodeoxyuridine, indicating their genesis in vitro. Using fluorescence-activated cell sorting, the E/nestin:EGFP⁺ and P/Tα1:hGFP⁺ cells were isolated to near purity, and matured antigenically and physiologically as neurons. Thus, the adult human hippocampus contains mitotically competent neuronal progenitors that can be selectively extracted. The isolation of these cells may provide a cellular substrate for re-populating the damaged or degenerated adult hippocampus.

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Targeted expression of baculovirus p35 caspase inhibitor in oligodendrocytes protects mice against autoimmune-mediated demyelination

Hisahara Shin, Araki Takashi, Sugiyama Fumihiro, Yagami Ken Ichi, Suzuki Misao, Abe Kuniya, Yamamura Ken Ichi, Miyazaki Jun Ichi, Momoi Takashi, Saruta Takao, Bernard Claude C A, Okano Hideyuki, Miura Masayuki

EMBO Journal 19 （ 3 ） 341 - 348 2000年02月

ISSN 0261-4189

The mechanisms underlying oligodendrocyte (OLG) loss and the precise roles played by OLG death in human demyelinating diseases such as multiple sclerosis (MS), and in the rodent model of MS, experimental autoimmune encephalomyelitis (EAE), remain to be elucidated. To clarify the involvement of OLG death in EAE, we have generated transgenic mice that express the baculovirus anti-apoptotic protein p35 in OLGs through the Cre-loxP system. OLGs from cre/p35 transgenic mice were resistant to tumor necrosis factor-α-, anti-Fas antibody- and interferon-γ-induced cell death. cre/p35 transgenic mice were resistant to EAE induction by immunization with the myelin oligodendrocyte glycoprotein. The numbers of infiltrating T cells and macrophages/microglia in the EAE lesions were significantly reduced, as were the numbers of apoptotic OLGs expressing the activated form of caspase-3. Thus, inhibition of apoptosis in OLGs by p35 expression alleviated the severity of the neurological manifestations observed in autoimmune demyelinating diseases.

Promoter-targeted selection and isolation of neural progenitor cells from the adult human ventricular zone

Roy Neeta S., Benraiss Abdellatif, Wang Su, Fraser Richard A R, Goodman Robert, Couldwell William T., Nedergaard Maiken, Kawaguchi Ayano, Okano Hideyuki, Goldman Steven A.

Journal of Neuroscience Research 59 （ 3 ） 321 - 331 2000年02月

ISSN 0360-4012

Adult humans, like their nonhuman mammalian counterparts, harbor persistent neural progenitor cells in the forebrain ventricular lining. In the absence of adequate surface markers, however, these cells have proven difficult to isolate for study. We have previously identified and selected neural progenitor cells from both the fetal and adult rodent ventricular zone (VZ), by sorting forebrain cells transfected with plasmid DNA encoding the gene for green fluorescent protein driven by the early neuronal promoter for Tα1 tubulin (P/Tα1:hGFP). We have now extended this approach by purifying both P/Tα1:hGFP tubulin-defined neuronal progenitors, as well as potentially less committed E/nestin:hGFP-defined neural progenitor cells, from the adult human VZ. The ventricular wall of the temporal horn of the lateral ventricle was dissected from temporal lobes obtained from four adult patients undergoing therapeutic lobectomy. These samples were dissociated, and the cultured cells transduced with either P/Tα1:hGFP or E/nestin:EGFP plasmid DNA. A week later, the cells were redissociated, selected via fluorescence- activated cell sorting (FACS) on the basis of neural promoter-driven GFP expression, and replated. The majority of these cells expressed the early neuronal protein βIII-tubulin upon FACS; within the week thereafter, most matured as morphologically evident neurons that coexpressed βIII-tubulin and microtubule-associated protein (MAP)-2. Many of these neurons had incorporated bromodeoxyuridine in vitro in the days before FACS, indicating their mitogenesis in vitro. Thus, the use of fluorescent transgenes under the control of early neural promoters permits the enrichment of neuronal progenitor cells from the adult human ventricular zone. The specific acquisition, in both purity and number, of residual neural progenitor cells from the adult human brain may now permit hitherto unfeasible studies of both their biology and practical application. (C) 2000 Wiley-Liss, Inc.

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神経幹細胞の分化制御機構と再生医学への応用

赤松和土，岡野栄之

医学のあゆみ 192 （ 8 ） 843-846 2000年02月

研究論文（学術雑誌）, 共著

Drob-1, a Drosophila member of the Bcl-2/CED-9 family that promotes cell death

Igaki Tatsushi, Kanuka Hirotaka, Inohara Naohiro, Sawamoto Kazunobu, Núñez Gabriel, Okano Hideyuki, Miura Masayuki

Proceedings of the National Academy of Sciences of the United States of America 97 （ 2 ） 662 - 667 2000年01月

ISSN 0027-8424

The Bcl-2/CED-9 family of proteins, which includes both antiapoptotic and proapoptotic members, plays key regulating roles in programmed cell death. We report here the identification and characterization of Drob-1, the first Drosophila member of the Bcl-2/CED-9 family to be isolated. Drob-1 contains four conserved Bcl-2 homology domains (BH1, BH2, BH3, and BH4) and a C-terminal hydrophobic domain. Ectopic expression of Drob-1 in the developing Drosophila eye resulted in a rough-eye phenotype. Furthermore, when overexpressed in Drosophila S2 cells, Drob-1 induced apoptosis accompanied by elevated caspase activity. This Drob-1-induced cell death, however, could not be antagonized by baculovirus p35, a broad-spectrum caspase inhibitor. Drob-1 was localized to the intracytoplasmic membranes, predominantly to the mitochondrial membranes, and a mutant Drob-1 lacking the hydrophobic C terminus lost both its mitochondrial localization and its proapoptotic activity. These results suggest that Drob-1 promotes cell death by inducing both caspase-dependent and -independent pathways at the mitochondria. Our identification of Drob-1 and further genetic analysis should provide increased understanding of the universal mechanisms by which the Bcl-2/CED-9 family members and other related proteins regulate apoptosis.

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GAL4/UAS-WGA system as a powerful tool for tracing Drosophila transsynaptic neural pathways

Tabuchi Katsuhiko, Sawamoto Kazunobu, Suzuki Emiko, Ozaki Koichi, Sone Masaki, Hama Chihiro, Tanifuji-Morimoto Takako, Yuasa Yoshihiro, Yoshihara Yoshihiro, Nose Akinao, Okano Hideyuki

Journal of Neuroscience Research 59 （ 1 ） 94 - 99 2000年01月

ISSN 0360-4012

Visualization of specific transsynaptic neural pathways is an indispensable technique for understanding the relationship between structure and function in the nervous system. Here, we demonstrate the application of the wheat germ agglutinin (WGA) transgene technique for tracing transsynaptic neural pathways in Drosophila. The intracellular localization of WGA was examined by immunoelectron microscopy. WGA signals were detected in granule- like structures in both the outer photoreceptor cells expressing WGA and the second-order laminar neurons. Misexpression of tetanus toxin (TNT), which inactivates N-synaptobrevin, in the outer photoreceptor cells resulted in the elimination of on/off transients in electroretinogram (ERG) recordings and in a great reduction in WGA transfer into laminar neurons, suggesting that anterograde WGA transsynaptic transfer is dependent mainly on synaptic transmission. Retrograde WGA transfer was also detected upon its forced expression in muscle cells. WGA primarily expressed in muscle cells was taken up by motoneuron axons and transported to their cell bodies in the ventral nerve cord, suggesting that WGA can trace motoneuronal pathways in combination with the muscle-specific GAL4 driver. Thus, the GAL4/UAS-WGA system should facilitate the dissection of the Drosophila neural circuit formation and/or synaptic activity in various regions and at various developmental stages.

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The bHLH gene Hes1 as a repressor of the neuronal commitment of CNS stem cells

Nakamura Yuki, Sakakibara Shin Ichi, Miyata Takaki, Ogawa Masaharu, Shimazaki Takuya, Weiss Samuel, Kageyama Ryoichiro, Okano Hideyuki

Journal of Neuroscience 20 （ 1 ） 283 - 293 2000年01月

ISSN 0270-6474

Hes1 is one of the basic helix-loop-helix transcription factors that regulate mammalian CNS development, and its loss- and gain-of-function phenotypes indicate that it negatively regulates neuronal differentiation. Here we report that Has1(-/-) mice expressed both early (TuJ1 and Hu) and late (MAP2 and Neurofilament) neuronal markers prematurely, and that there were approximately twice the normal number of neurons in the Hes1 (-/-) brain during early neural development. However, immunochemical analyses of sections and dissociated cells using neural progenitor markers, including nestin, failed to detect any changes in Hes1 (-/-) progenitor population. Therefore, further characterization of neural progenitor cells that discriminated between multipotent and monopotent cells was performed using two culture methods, low-density culture, and a neurosphere assay. We demonstrate that the self-renewal activity of multipotent progenitor cells was reduced in the Hes1 (-/-) brain, and that their subsequent commitment to the neuronal lineage was accelerated. The Hes1 (-/-) neuronal progenitor cells were functionally abnormal, in that they divided, on average, only once, and then generated two neurons, (instead of one progenitor cell and one neuron), whereas wild-type progenitor cells divided more. In addition, some Hes1(-/-) progenitors followed an apoptotic fate. The overproduction of neurons in the early Hes1(-/-) brains may reflect this premature and immediate generation of neurons as well as a net increase in the number of neuronal progenitor cells. Taken together, we conclude that Hes1 is important for maintaining the self- renewing ability of progenitors and for repressing the commitment of multipotent progenitor cells to a neuronal fate, which is critical for the correct number of neurons to be produced and for the establishment of normal neuronal function.

Dissection of signaling cascades through gp130 in vivo

Ohtani Takuya, Ishihara Katsuhiko, Atsumi Toru, Nishida Keigo, Kaneko Yukiko, Miyata Takaki, Itoh Shousaku, Narimatsu Masahiro, Maeda Hisoka, Fukada Toshiyuki, Itoh Motoyuki, Okano Hideyuki, Hibi Masahiko, Hirano Toshio

Immunity 12 （ 1 ） 95 - 105 2000年01月

ISSN 1074-7613

We generated a series of knockin mouse lines, in which the cytokine receptor gp130-dependent STAT3 and/or SHP2 signals were disrupted, by replacing the mouse gp130 gene with human gp130 mutant cDNAs. The SHP2 signal-deficient mice (gp130(F759/F759)) were born normal but displayed splenomegaly and lymphadenopathy and an enhanced acute phase reaction. In contrast, the STAT3 signal-deficient mice (gp130(FXXQ/FXXQ)) died perinatally, like the gp130-deficient mice (gp130(D/D)). The gp13(F759/F759) mice showed prolonged gp130-induced STAT3 activation, indicating a negative regulatory role for SHP2. Th1 -type cytokine production and IgG2a and IgG2b production were increased in the gp13(F759/F759) mice, while they were decreased in the gp130(FXXQ/FXXQ) immune system. These results indicate that the balance of positive and negative signals generated through gp130 regulates the immune responses.

Regulation of neural development mediated by neural RNA binding proteins

Akamatsu W., Okano H.

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme 45 （ 3 Suppl ） 227 - 232 2000年

ISSN 0039-9450

Identification and characterization of human brain tumor antigens: a potential target for specific immunotherapy and diagnostic marker

Toda M, Iizuka Y, Takahashi S, Fujita T, Ikeda E, Yoshida K, Kawase T, Okano H, Uyemura K, Kawakami Y

Proceedings of the American Association for Cancer Research 41 710 2000年

研究論文（学術雑誌）, 共著

Musashi 1;An evolutionally conserved marker forCNS progenitor cells including neural stem cells.

Kaneko Yukiko, Imai T, Nakamura Y, Sawamoto K, Ogawa Yuuto, Toyama Yoshiaki, Miyata T, Okano Hideyuki

Developmental Neuroscience 22 139-153 2000年

研究論文（学術雑誌）, 共著

Neural stem cells

Okano H.

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme 45 （ 13 Suppl ） 2063 - 2077 2000年

ISSN 0039-9450

Role of caspase-1 subfamily in cytotoxic cytokine-induced oligodendrocyte cell death

Hisahara S., Takano R., Shoji S., Okano H., Miura M.

Journal of Neural Transmission, Supplement （ 58 ） 135 - 142 2000年

ISSN 0303-6995

Oligodendrocytes are myelin forming cells in mammalian central nervous system. About 50% of oligodendrocytes (OLGs) undergo cell death in normal development. In addition, OLG cell deaths have been observed in demyelinating diseases including multiple sclerosis (MS). Clinical observations and in vitro cell culture studies have suggested that cytokines mediate OLG cell damage in multiple sclerosis (MS). Among the cytokines, tumor necrosis factor (TNF) is thought to be one of the mediators responsible for the damage of OLGs in MS. The administration of TNF-α to primary cultures of OLGs induced DNA fragmentation, and significantly decreased the number of live OLGs. Chemical inhibitors Ac-YVAD-CHO (a specific inhibitor of caspase-1 (ICE)-like proteases) enhanced the survival of TNF-α treated OLGs better than Ac-DEVD-CHO (a specific inhibitor of caspase-3 (CPP32)-like proteases). These results indicate that caspase-1-mediated cell-death pathway are activated in TNF-induced OLG cell death. Caspase-11 is involved in activation of caspase-1. Oligodendrocytes from caspase-11-deficient mice are partially resistant to TNF-induced OLG cell death. Our results suggest that the inhibition of caspase-1 sufamily may be a novel therapeutic approach to treat MS.

Neural stem cells

Okano H.

Japanese Journal of Psychopharmacology 20 （ 1 ） 21 - 26 2000年

ISSN 1340-2544

Neural stem cells (NSCs) are multipotential progenitor cells that have self-renewal activities. A single NSC is capable of generating various kinds of cells within the CNS, including neurons, astrocytes, and oligodendrocytes. Because of these characteristics, there is an increasing interest in NSCs and neural progenitor cells from the aspects of both basic developmental biology and therapeutic applications for damaged brain. By understanding the nature of NSCs present in the CNS, extracellular factors and signal transduction cascades involved in the differentiation and maintenance of NSCs, population dynamics and localization of NSCs in embryonic and adult brains, prospective identification and isolation of NSCs, and induction of NSCs into particular neuronal phenotypes, it would be possible to develop a feasible strategy to manipulate cells in situ to treat damaged brain.

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岡野 栄之

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