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金子 奈穂子カネコ ナオコ

所属部署医学研究科神経発達・再生医学分野
職名准教授
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Last Updated :2020/05/26

研究者基本情報

学位

  • 博士(医学), 山梨大学

所属学協会

  • Society for Neuroscience
  • 日本精神神経学会
  • 日本分子生物学会
  • 日本炎症・再生医学会
  • 日本再生医療学会
  • 日本神経科学学会
  • 日本神経化学会

経歴

  •   2018年04月 - 現在, 名古屋市立大学医学研究科, 再生医学分野, 准教授
  •   2013年08月 - 2018年03月, 名古屋市立大学医学研究科, 再生医学分野, 講師
  •   2009年04月 - 2013年07月, 名古屋市立大学医学研究科, 再生医学分野, 助教
  •   2007年04月 - 2009年03月, 名古屋市立大学大学院医学研究科, 再生医学分野, 井上科学振興財団「井上フェロー」
  •   2004年04月 - 2007年03月, 山梨大学大学院医学工学総合教育部博士課程
  •   2007年03月, 博士課程修了、博士(医学)取得

研究活動情報

研究分野

  • ライフサイエンス, 神経科学一般

研究キーワード

    包括脳ネットワーク, 再生医学, 神経科学, 脳神経疾患, 脳・神経, 発生・分化, ニューロン新生, 脳室下帯, Slit, 新生ニューロン, 分化, 発生, アストロサイト, 細胞移動, 老化, Robo, ニューロン再生, 脳梗塞

論文

  • Dynamic Changes in the Neurogenic Potential in the Ventricular-Subventricular Zone of Common Marmoset during Postnatal Brain Development., Mariyam Akter, Naoko Kaneko, Vicente Herranz-Pérez, Sayuri Nakamura, Hisashi Oishi, Jose Manuel García-Verdugo, Kazunobu Sawamoto, Cerebral cortex (New York, N.Y. : 1991),   2020年02月28日, 査読有り, Even after birth, neuronal production continues in the ventricular-subventricular zone (V-SVZ) and hippocampus in many mammals. The immature new neurons ("neuroblasts") migrate and then mature at their final destination. In humans, neuroblast production and migration toward the neocortex and the olfactory bulb (OB) occur actively only for a few months after birth and then sharply decline with age. However, the precise spatiotemporal profiles and fates of postnatally born neurons remain unclear due to methodological limitations. We previously found that common marmosets, small nonhuman primates, share many features of V-SVZ organization with humans. Here, using marmosets injected with thymidine analogue(s) during various postnatal periods, we demonstrated spatiotemporal changes in neurogenesis during development. V-SVZ progenitor proliferation and neuroblast migration toward the OB and neocortex sharply decreased by 4 months, most strikingly in a V-SVZ subregion from which neuroblasts migrated toward the neocortex. Postnatally born neurons matured within a few months in the OB and hippocampus but remained immature until 6 months in the neocortex. While neurogenic activity was sustained for a month after birth, the distribution and/or differentiation diversity was more restricted in 1-month-born cells than in the neonatal-born population. These findings shed light on distinctive features of postnatal neurogenesis in primates.
  • Dynamic changes in ultrastructure of the primary cilium in migrating neuroblasts in the postnatal brain., Matsumoto M, Sawada M, García-González D, Herranz-Pérez V, Ogino T, Bang Nguyen H, Quynh Thai T, Narita K, Kumamoto N, Ugawa S, Saito Y, Takeda S, Kaneko N, Khodosevich K, Monyer H, Manuel García-Verdugo J, Ohno N, Sawamoto K, The Journal of Neuroscience, in press, (in press) ,   2019年12月, 査読有り
  • Blood vessels as a scaffold for neuronal migration., Fujioka T, Kaneko N, Sawamoto K, Neurochemistry International, 126, 69 - 73,   2019年06月, 査読有り, 招待有り
  • Ventricular-subventricular zone fractones are speckled basement membranes that function as a neural stem cell niche., Sato Y, Kiyozumi D, Futaki S, Nakano I, Shimono C, Kaneko N, Ikawa M, Okabe M, Sawamoto K, Sekiguchi K, Molecular Biology of the Cell, 30, (1) 56 - 68,   2019年01月, 査読有り
  • New neurons use Slit-Robo signaling to migrate through the glial meshwork and approach a lesion for functional regeneration., Kaneko N, Herranz-Pérez V, Otsuka T, Sano H, Ohno N, Omata T, Nguyen HB, Thai TQ, Nambu A, Kawaguchi Y, García-Verdugo JM, Sawamoto K, Science Advances, 4, (12) ,   2018年12月, 査読有り
  • Shootin1b Mediates a Mechanical Clutch to Produce Force for Neuronal Migration., Minegishi T, Uesugi Y, Kaneko N, Yoshida W, Sawamoto K, Inagaki N, Cell Reports, 25, (3) 624 - 639,   2018年10月, 査読有り
  • Go with the flow: Cerebrospinal fluid flow regulates neural stem cell proliferation., Kaneko N, Sawamoto K, Cell Stem Cell, in press,   2018年06月, 査読有り, 招待有り
  • Detachment of Chain-Forming Neuroblasts by Fyn-Mediated Control of cell-cell Adhesion in the Postnatal Brain., Fujikake K, Sawada M, Hikita T, Seto Y, Kaneko N, Herranz-Pérez V, Dohi N, Homma N, Osaga S, Yanagawa Y, Akaike T, García-Verdugo JM, Hattori M, Sobue K, Sawamoto K, The Journal of Neuroscience, 38, (19) 4598 - 4609,   2018年05月, 査読有り
  • Radial glial fibers support neuronal migration and regeneration after neonatal brain injury., Jinnou H, Sawada M, Kawase K, Kaneko N, Herranz-Pérez V, Miyamoto T, Kawaue T, Miyata T, Tabata Y, Akaike T, García-Verdugo JM, Ajioka I, Saitoh S, Sawamoto K, Cell Stem Cell,, 22, 128 - 137,   2018年01月, 査読有り
  • Unique Organization of the Nuclear Envelope in the Post-natal Quiescent Neural Stem Cells, Arantxa Cebrian-Silla, Clara Alfaro-Cervello, Vicente Herranz-Perez, Naoko Kaneko, Dae Hwi Park, Kazunobu Sawamoto, Arturo Alvarez-Buylla, Daniel A. Lim, Jose Manuel Garcia-Verdugo, STEM CELL REPORTS, 9, (1) 203 - 216,   2017年07月, 査読有り, Neural stem cells (B1 astrocytes; NSCs) in the adult ventricular-subventricular-zone (V-SVZ) originate in the embryo. Surprisingly, recent work has shown that B1 cells remain largely quiescent. They are reactivated postnatally to function as primary progenitors for neurons destined for the olfactory bulb and some corpus callosum oligodendrocytes. The cellular and molecular properties of quiescent B1 cells remain unknown. Here we found that a subpopulation of B1 cells has a unique nuclear envelope invagination specialization similar to envelope-limited chromatin sheets (ELCS), reported in certain lymphocytes and some cancer cells. Using molecular markers, [3 H] thymidine birth-dating, and Ara-C, we found that B1 cells with ELCS correspond to quiescent NSCs. ELCS begin forming in embryonic radial glia cells and represent a specific nuclear compartment containing particular epigenetic modifications and telomeres. These results reveal a unique nuclear compartment in quiescent NSCs, which is useful for identifying these primary progenitors and study their gene regulation.
  • Mechanisms of neuronal migration in the adult brain, Naoko Kaneko, Masato Sawada, Kazunobu Sawamoto, JOURNAL OF NEUROCHEMISTRY, 141, (6) 835 - 847,   2017年06月, 査読有り, Adult neurogenesis was first observed nearly 60 years ago, and it has since grown into an important neurochemistry research field. Much recent research has focused on the treatment of brain diseases through neuronal regeneration with endogenously generated neurons. In the adult brain, immature neurons called neuroblasts are continuously generated in the ventricular-subventricular zone (V-SVZ). These neuroblasts migrate rapidly through the rostral migratory stream to the olfactory bulb, where they mature and are integrated into the neuronal circuitry. After brain insult, some of the neuroblasts in the V-SVZ migrate toward the lesion to repopulate the injured tissue. This notable migratory capacity of V-SVZ-derived neuroblasts is important for efficiently regenerating neurons in remote areas of the brain. As these neurons migrate for long distances through adult brain tissue, they are supported by various guidance cues and structures that act as scaffolds. Some of these mechanisms are unique to neuroblast migration in the adult brain, and are not involved in migration in the developing brain. Here, we review the latest findings on the mechanisms of neuroblast migration in the adult brain under physiological and pathological conditions, and discuss various issues that still need to be resolved.
  • Angiogenic Biomaterials for Brain Ischemia Using Affinity-Immobilized VEGF on Laminin Porous Sponge., Oshikawa M, Okada K, Kaneko N, Sawamoto K, Ajioka I, Advanced Healthcare Materials, 6, (11) ,   2017年06月, 査読有り
  • β1 integrin signaling promotes neuronal migration along vascular scaffolds in the post-stroke brain., Fujioka T, Kaneko N, Ajioka I, Nakaguchi K, Omata T, Ohba H, Fässler R, García-Verdugo JM, Sekiguchi K, Matsukawa N, Sawamoto K, EBioMedicine, 16, 195 - 203,   2017年02月, 査読有り
  • Genome-Wide Association Study Identifies ZNF354C Variants Associated with Depression from Interferon-Based Therapy for Chronic Hepatitis C, Kayoko Matsunami, Nao Nishida, Naoko Kaneko, Kazuho Ikeo, Licht Toyo-oka, Hiroshi Takeuchi, Kentaro Matsuura, Akihiro Tamori, Hideyuki Nomura, Hitoshi Yoshiji, Masatoshi Imamura, Naohiko Masaki, Tatsuro Hayakawa, Tatsuya Ide, Noritomo Shimada, Fusao Ikeda, Keisuke Hino, Shuhei Nishiguchi, Chiaki Okuse, Shunsuke Nojiri, Kazunobu Sawamoto, Katsushi Tokunaga, Takashi Joh, Yasuhito Tanaka, PLOS ONE, 11, (10) ,   2016年10月, 査読有り, The therapeutic use of interferon (IFN) is known to cause depression that frequently interrupts treatment. To identify genetic variants associated with IFN-induced depression, we conducted a genome-wide association study (GWAS) of 224 Japanese chronic hepatitis C patients receiving IFN-based therapy in a multicenter prospective study and stratified them into two groups according to the Beck Depression Inventory, Second Edition (BDI-II) score. In the GWAS stage, we selected 42 candidate single nucleotide polymorphisms (SNPs) to perform replication analysis in an independent set of 160 subjects. The SNP rs1863918 in strong linkage disequilibrium with SNPs located around the Zinc finger 354C (ZNF354C) gene on chromosome 5 showed a significant association when the results of GWAS and replication were combined (odds ratio = 2.55, P = 7.89x10(-8) in the allele frequency model), suggesting that the rs1863918 T allele was associated with IFN-induced depression. Furthermore, logistic regression analysis showed that rs1863918 T allele, a history of depression, and younger age were independent predictive factors for IFN-induced depression. Interestingly, western blotting and immunofluorescence showed that ZNF354C was highly expressed in the hippocampus in mice, a region implicated in the pathology of psychiatric symptoms. In conclusion, we identified rs1863918 as significantly associated with IFN-induced depression, and revealed that the candidate gene ZNF354C is highly expressed in the hippocampus of mice. Our data might be useful for elucidating the pathogenic mechanisms of depression induced by drugs including IFN.
  • Characterization of multiciliated ependymal cells that emerge in the neurogenic niche of the aged zebrafish brain, Takashi Ogino, Masato Sawada, Hiroshi Takase, Chiemi Nakai, Vicente Herranz-Perez, Arantxa Cebrian-Silla, Naoko Kaneko, Jose Manuel Garcia-Verdugo, Kazunobu Sawamoto, JOURNAL OF COMPARATIVE NEUROLOGY, 524, (15) 2982 - 2992,   2016年10月, 査読有り, In mammals, ventricular walls of the developing brain maintain a neurogenic niche, in which radial glial cells act as neural stem cells (NSCs) and generate new neurons in the embryo. In the adult brain, the neurogenic niche is maintained in the ventricular-subventricular zone (V-SVZ) of the lateral wall of lateral ventricles and the hippocampal dentate gyrus. In the neonatal V-SVZ, radial glial cells transform into astrocytic postnatal NSCs and multiciliated ependymal cells. On the other hand, in zebrafish, radial glial cells continue to cover the surface of the adult telencephalic ventricle and maintain a higher neurogenic potential in the adult brain. However, the cell composition of the neurogenic niche of the aged zebrafish brain has not been investigated. Here we show that multiciliated ependymal cells emerge in the neurogenic niche of the aged zebrafish telencephalon. These multiciliated cells appear predominantly in the dorsal part of the ventral telencephalic ventricular zone, which also contains clusters of migrating new neurons. Scanning electron microscopy and live imaging analyses indicated that these multiple cilia beat coordinately and generate constant fluid flow within the ventral telencephalic ventricle. Analysis of the cell composition by transmission electron microscopy revealed that the neurogenic niche in the aged zebrafish contains different types of cells, with ultrastructures similar to those of ependymal cells, transit-amplifying cells, and migrating new neurons in postnatal mice. These data suggest that the transformation capacity of radial glial cells is conserved but that its timing is different between fish and mice. J. Comp. Neurol. 524:2982-2992, 2016. (c) 2016 Wiley Periodicals, Inc.
  • Minocycline treatment ameliorates interferon-alpha- induced neurogenic defects and depression-like behaviors in mice., Zheng LS, Kaneko N, Sawamoto K, corresponding author, Frontiers in Cellular Neuroscience, 9, (5) ,   2015年01月, 査読有り
  • Mechanisms for Interferon-α-Induced Depression and Neural Stem Cell Dysfunction., Zheng LS, Hitoshi S, Kaneko N, Takao K, Miyakawa T, Tanaka Y, Xia H, Kalinke U, Kudo K, Kanba S, Ikenaka K, Sawamoto K, equal contribution, corresponding author, Stem cell reports, 3, (1) 73 - 84,   2014年07月, 査読有り
  • Enhancement of ventricular-subventricular zone-derived neurogenesis and oligodendrogenesis by erythropoietin and its derivatives, Naoko Kaneko, Eisuke Kako, Kazunobu Sawamoto, FRONTIERS IN CELLULAR NEUROSCIENCE, 7, (NOV) ,   2013年11月, 査読有り, In the postnatal mammalian brain, stem cells in the ventricular-subventricular zone (V-SVZ) continuously generate neuronal and glial cells through out life. Genetic labeling of cells of specific lineages have demonstrated that the V-SVZ is an important source of the neuroblasts and/or oligodendrocyte progenitor cells (OPCs) that migrate toward injured brain are asin response to several types of insult, including ischemia and demyelinating diseases. However, this spontaneous regeneration is insufficient for complete structural and functional restoration of the injured brain, so interventions to enhance these processes are sought for clinical applications. Erythropoietin (EPO), a clinically applied erythropoietic factor, is reported to have cytoprotective effects in various kinds of insult in the central nervous system. Moreover, recent studies suggest that EPO promotes the V-SVZ-derived neurogenesis and oligodendrogenesis. EPO increases the proliferation of progenitors in the V-SVZ and/or the migration and differentiation of their progenies in and around injured areas, depending on the dosage, timing, and duration of treatment, as well as the type of animal model used. On the other hand, EPO has undesirable side effects, including thrombotic complications. We recently demonstrated that a 2-week treatment with the EPO derivative asialo-EPO promotes the differentiation of V-SVZ-derived OPCs into myelin-forming mature oligodendrocytes in the injured white matter of neonatal mice without causing erythropoiesis. Here we present an overview of the multifaceted effects of EPO and its derivatives in the V-SVZ and discuss the possible applications of these molecules in regenerative medicine.
  • Human Dental Pulp-Derived Stem Cells Protect Against Hypoxic-Ischemic Brain Injury in Neonatal Mice, Mari Yamagata, Akihito Yamamoto, Eisuke Kako, Naoko Kaneko, Kohki Matsubara, Kiyoshi Sakai, Kazunobu Sawamoto, Minoru Ueda, STROKE, 44, (2) 551 - 554,   2013年02月, 査読有り, Background and Purpose-Perinatal hypoxia-ischemia (HI) has high rates of neurological deficits and mortality. So far, no effective treatment for HI brain injury has been developed. In this study, we investigated the therapeutic effects of stem cells from human exfoliated deciduous teeth (SHED) for the treatment of neonatal HI brain injury. Methods-Unilateral HI was induced in postnatal day 5 (P5) mice. Twenty-four hours later, SHED, human skin fibroblasts, or serum-free conditioned medium derived from these cells was injected into the injured brain. The effects of cell transplantation or conditioned medium injection on the animals' neurological and pathophysiological recovery were evaluated. Results-Transplanted SHED, but not fibroblasts, significantly reduced the HI-induced brain-tissue loss and improved neurological function. SHED also improved the survival of the HI mice. The engrafted SHED rarely differentiated into neural lineages; however, their transplantation inhibited the expression of proinflammatory cytokines, increased the expression of anti-inflammatory ones, and significantly reduced apoptosis. Notably, the intracerebral administration of SHED-conditioned medium also significantly improved the neurological outcome, inhibited apoptosis, and reduced tissue loss. Conclusions-SHED transplantation into the HI-injured brain resulted in remarkable neurological and pathophysiological recovery. Our findings indicate that paracrine factors derived from SHED support a neuroprotective microenvironment in the HI brain. SHED graft and SHED-conditioned medium may provide a novel neuroprotective therapy for HI. (Stroke. 2013;44:551-554.)
  • Subventricular Zone-Derived Oligodendrogenesis in Injured Neonatal White Matter in Mice Enhanced by a Nonerythropoietic Erythropoietin Derivative, Eisuke Kako, Naoko Kaneko, Mineyoshi Aoyama, Hideki Hida, Hirohide Takebayashi, Kazuhiro Ikenaka, Kiyofumi Asai, Hajime Togari, Kazuya Sobue, Kazunobu Sawamoto, STEM CELLS, 30, (10) 2234 - 2247,   2012年10月, 査読有り, Perinatal hypoxia-ischemia (HI) frequently causes white-matter injury, leading to severe neurological deficits and mortality, and only limited therapeutic options exist. The white matter of animal models and human patients with HI-induced brain injury contains increased numbers of oligodendrocyte progenitor cells (OPCs). However, the origin and fates of these OPCs and their potential to repair injured white matter remain unclear. Here, using cell-type- and region-specific genetic labeling methods in a mouse HI model, we characterized the Olig2-expressing OPCs. We found that after HI, Olig2+ cells increased in the posterior part of the subventricular zone (pSVZ) and migrated into the injured white matter. However, their oligodendrocytic differentiation efficiency was severely compromised compared with the OPCs in normal tissue, indicating the need for an intervention to promote their differentiation. Erythropoietin (EPO) treatment is a promising candidate, but it has detrimental effects that preclude its clinical use for brain injury. We found that long-term postinjury treatment with a nonerythropoietic derivative of EPO, asialo-erythropoietin, promoted the maturation of pSVZ-derived OPCs and the recovery of neurological function, without affecting hematopoiesis. These results demonstrate the limitation and potential of endogenous OPCs in the pSVZ as a therapeutic target for treating neonatal white-matter injury. STEM Cells2012;30:22342247
  • Growth factors released from gelatin hydrogel microspheres increase new neurons in the adult mouse brain., Nakaguchi K, Jinnou H, Kaneko N, Sawada M, Hikita T, Saitoh S, Tabata Y, Sawamoto K, Stem cells international, 2012,   2012年10月, 査読有り
  • A role for mDia, a Rho-regulated actin nucleator, in tangential migration of interneuron precursors, Ryota Shinohara, Dean Thumkeo, Hiroshi Kamijo, Naoko Kaneko, Kazunobu Sawamoto, Keisuke Watanabe, Hirohide Takebayashi, Hiroshi Kiyonari, Toshimasa Ishizaki, Tomoyuki Furuyashiki, Shuh Narumiya, NATURE NEUROSCIENCE, 15, (3) 373 - U193,   2012年03月, 査読有り, In brain development, distinct types of migration, radial migration and tangential migration, are shown by excitatory and inhibitory neurons, respectively. Whether these two types of migration operate by similar cellular mechanisms remains unclear. We examined neuronal migration in mice deficient in mDia1 (also known as Diap1) and mDia3 (also known as Diap2), which encode the Rho-regulated actin nucleators mammalian diaphanous homolog 1 (mDia1) and mDia3. mDia deficiency impaired tangential migration of cortical and olfactory inhibitory interneurons, whereas radial migration and consequent layer formation of cortical excitatory neurons were unaffected. mDia-deficient neuroblasts exhibited reduced separation of the centrosome from the nucleus and retarded nuclear translocation. Concomitantly, anterograde F-actin movement and F-actin condensation at the rear, which occur during centrosomal and nuclear movement of wild-type cells, respectively, were impaired in mDia-deficient neuroblasts. Blockade of Rho-associated protein kinase (ROCK), which regulates myosin II, also impaired nuclear translocation. These results suggest that Rho signaling via mDia and ROCK critically regulates nuclear translocation through F-actin dynamics in tangential migration, whereas this mechanism is dispensable in radial migration.
  • アシアロエリスロポエチンの脳低酸素虚血傷害に対する治療効果, 加古 英介, 金子 奈穂子, 青山 峰芳, 飛田 秀樹, 戸苅 創, 浅井 清文, 祖父江 和哉, 澤本 和延, Nagoya Medical Journal, 52, (2) 164 - 165,   2012年02月
  • Growth Factors Released from Gelatin Hydrogel Microspheres Increase New Neurons in the Adult Mouse Brain, Kanako Nakaguchi, Hideo Jinnou, Naoko Kaneko, Masato Sawada, Takao Hikita, Shinji Saitoh, Yasuhiko Tabata, Kazunobu Sawamoto, STEM CELLS INTERNATIONAL, 2012, 1 - 7,   2012年, 査読有り, Recent studies have shown that new neurons are continuously generated by endogenous neural stem cells in the subventricular zone (SVZ) of the adult mammalian brain. Some of these new neurons migrate to injured brain tissues and differentiate into mature neurons, suggesting that such new neurons may be able to replace neurons lost to degenerative disease or injury and improve or repair neurological deficits. Here, we tested whether delivering growth factors via gelatin hydrogel microspheres would support neurogenesis in the SVZ. Insulin-like growth factor-1 (IGF-1)-containing microspheres increased the number of new neurons in the SVZ. Hepatocyte growth factor (HGF)-containing microspheres increased the number of new neurons migrating from the SVZ towards the injured striatum in a stroke model in mouse. These results suggest that the strategy of using gelatin hydrogel microspheres to achieve the sustained release of growth factors holds promise for the clinical regeneration of damaged brain tissues from endogenous neural stem cells in the adult SVZ.
  • A subtype-specific critical period for neurogenesis in the postnatal development of mouse olfactory glomeruli., Yasuko Kato, Naoko Kaneko, Masato Sawada, Keishi Ito, Sousuke Arakawa, Shingo Murakami, Kazunobu Sawamoto, PloS one, 7, (11) ,   2012年, 査読有り, Sensory input is essential for the normal development of sensory centers in the brain, such as the somatosensory, visual, auditory, and olfactory systems. Visual deprivation during a specific developmental stage, called the critical period, results in severe and irreversible functional impairments in the primary visual cortex. Olfactory deprivation in the early postnatal period also causes significant developmental defects in the olfactory bulb, the primary center for olfaction. Olfactory bulb interneurons are continuously generated from neural stem cells in the ventricular-subventricular zone, suggesting that the olfactory system has plasticity even in adulthood. Here, we investigated the effect of transient neonatal olfactory deprivation on the addition of interneurons to the glomerular layer of the adult mouse olfactory bulb. We found that the addition of one subtype of interneurons was persistently inhibited even after reopening the naris. BrdU pulse-chase experiments revealed that the neonatal olfactory deprivation predominantly affected an early phase in the maturation of this neuronal subtype in the olfactory bulb. Subjecting the mice to odor stimulation for 6 weeks after naris reopening resulted in significant recovery from the histological and functional defects caused by the olfactory deprivation. These results suggest that a subtype-specific critical period exists for olfactory bulb neurogenesis, but that this period is less strict and more plastic compared with the critical periods for other systems. This study provides new insights into the mechanisms of postnatal neurogenesis and a biological basis for the therapeutic effect of olfactory training.
  • Sensory Input Regulates Spatial and Subtype-Specific Patterns of Neuronal Turnover in the Adult Olfactory Bulb, Masato Sawada, Naoko Kaneko, Hiroyuki Inada, Hiroaki Wake, Yasuko Kato, Yuchio Yanagawa, Kazuto Kobayashi, Tomomi Nemoto, Junichi Nabekura, Kazunobu Sawamoto, JOURNAL OF NEUROSCIENCE, 31, (32) 11587 - 11596,   2011年08月, 査読有り, Throughout life, new neurons are added and old ones eliminated in the adult mouse olfactory bulb. Previous studies suggested that olfactory experience controls the process by which new neurons are integrated into mature circuits. Here we report novel olfactory-experience-dependent mechanisms of neuronal turnover. Using two-photon laser-scanning microscopy and sensory manipulations in adult live mice, we found that the neuronal turnover was dynamically controlled by olfactory input in a neuronal subtype-specific manner. Olfactory input enhanced this turnover, which was characterized by the reiterated use of the same positions in the glomeruli by new neurons. Our results suggest that olfactory-experience-dependent modification of neuronal turnover confers structural plasticity and stability on the olfactory bulb.
  • Girdin Is an Intrinsic Regulator of Neuroblast Chain Migration in the Rostral Migratory Stream of the Postnatal Brain, Yun Wang, Naoko Kaneko, Naoya Asai, Atsushi Enomoto, Mayu Isotani-Sakakibara, Takuya Kato, Masato Asai, Yoshiki Murakumo, Haruko Ota, Takao Hikita, Takashi Namba, Keisuke Kuroda, Kozo Kaibuchi, Guo-li Ming, Hongjun Song, Kazunobu Sawamoto, Masahide Takahashi, JOURNAL OF NEUROSCIENCE, 31, (22) 8109 - 8122,   2011年06月, 査読有り, In postnatally developing and adult brains, interneurons of the olfactory bulb (OB) are continuously generated at the subventricular zone of the forebrain. The newborn neuroblasts migrate tangentially to the OB through a well defined pathway, the rostral migratory stream (RMS), where the neuroblasts undergo collective migration termed "chain migration." The cell-intrinsic regulatory mechanism of neuroblast chain migration, however, has not been uncovered. Here we show that mice lacking the actin-binding Akt substrate Girdin (a protein that interacts with Disrupted-In-Schizophrenia 1 to regulate neurogenesis in the dentate gyrus) have profound defects in neuroblast chain migration along the RMS. Analysis of two gene knock-in mice harboring Girdin mutants identified unique amino acid residues in Girdin's C-terminal domain that are responsible for the regulation of neuroblast chain migration but revealed no apparent requirement of Girdin phosphorylation by Akt. Electron microscopic analyses demonstrated the involvement of Girdin in neuroblast cell-cell interactions. These findings suggest that Girdin is an important intrinsic factor that specifically governs neuroblast chain migration along the RMS.
  • Strategies for regenerating striatal neurons in the adult brain by using endogenous neural stem cells., Nakaguchi K, Masuda H, Kaneko N, Sawamoto K, Neurology research international, 2011,   2011年06月, 査読有り
  • Prospects and Limitations of Using Endogenous Neural Stem Cells for Brain Regeneration, Naoko Kaneko, Eisuke Kako, Kazunobu Sawamoto, GENES, 2, (1) 107 - 130,   2011年03月, 査読有り, Neural stem cells (NSCs) are capable of producing a variety of neural cell types, and are indispensable for the development of the mammalian brain. NSCs can be induced in vitro from pluripotent stem cells, including embryonic stem cells and induced-pluripotent stem cells. Although the transplantation of these exogenous NSCs is a potential strategy for improving presently untreatable neurological conditions, there are several obstacles to its implementation, including tumorigenic, immunological, and ethical problems. Recent studies have revealed that NSCs also reside in the adult brain. The endogenous NSCs are activated in response to disease or trauma, and produce new neurons and glia, suggesting they have the potential to regenerate damaged brain tissue while avoiding the above-mentioned problems. Here we present an overview of the possibility and limitations of using endogenous NSCs in regenerative medicine.
  • Roles of mDia isoforms, a Rho effector, in neuroblast migration, Ryota Shinohara, Dean Thumkeo, Hiroshi Kamijo, Naoko Kaneko, Kazunobu Sawamoto, Keisuke Watanabe, Hirohide Takebayashi, Toshimasa Ishizaki, Tomoyuki Furuyashiki, Shuh Narumiya, JOURNAL OF PHARMACOLOGICAL SCIENCES, 115, 133P - 133P,   2011年, 査読有り
  • mDia, an actin nucleator and a Rho effector, is critical for tangential migration of cortical and olfactory bulb inhibitory interneuron precursors, Ryota Shinohara, Dean Thumkeo, Hiroshi Kamijo, Naoko Kaneko, Kazunobu Sawamoto, Keisuke Watanabe, Hirohide Takebayashi, Hiroshi Kiyonari, Toshimasa Ishizaki, Tomoyuki Furuyashiki, Shuh Narumiya, NEUROSCIENCE RESEARCH, 71, E130 - E130,   2011年, 査読有り
  • Promotion of neuronal migration towards the injured mouse cerebral cortex using sustained release of chemoattractant from gelatin hydrogel microspheres, Hiroshi Masuda, Naoko Kaneko, Eisuke Kako, Takao Hikita, Yasuhiko Tabata, Kazunobu Sawamoto, NEUROSCIENCE RESEARCH, 71, E338 - E339,   2011年, 査読有り
  • Development and analysis of less invasive transient middle cerebral artery occlusion model on non-human primate, Koichi Hara, Satoshi Inoue, Jun Muto, Naoko Kaneko, Fumika Toyoda, Keigo Hikishima, Toshio Itoh, Kazunobu Sawamoto, Kazunari Yoshida, Takeshi Kawase, Hideyuki Okano, NEUROSCIENCE RESEARCH, 71, E403 - E404,   2011年
  • Directional migration of new neurons generated by transplanted human iPS cell-derived neural stem cells in the striatum of a mouse stroke model, Kanako Nakaguchi, Naoko Kaneko, Mineyoshi Aoyama, Yohei Okada, Kiyofumi Asai, Hideyuki Okano, Kazunobu Sawamoto, NEUROSCIENCE RESEARCH, 71, E338 - E338,   2011年
  • New Neurons Clear the Path of Astrocytic Processes for Their Rapid Migration in the Adult Brain, Naoko Kaneko, Oscar Marin, Masato Koike, Yuki Hirota, Yasuo Uchiyama, Jane Y. Wu, Qiang Lu, Marc Tessier-Lavigne, Arturo Alvarez-Buylla, Hideyuki Okano, John L. R. Rubenstein, Kazunobu Sawamoto, NEURON, 67, (2) 213 - 223,   2010年07月, 査読有り, In the long-range neuronal migration of adult mammals, young neurons travel from the subventricular zone to the olfactory bulb, a long journey (millimeters to centimeters, depending on the species). How can these neurons migrate through the dense meshwork of neuronal and glial processes of the adult brain parenchyma? Previous studies indicate that young neurons achieve this by migrating in chains through astrocytic tunnels. Here, we report that young migrating neurons actively control the formation and maintenance of their own migration route. New neurons secrete the diffusible protein Slit1, whose receptor, Robo, is expressed on astrocytes. We show that the Slit-Robo pathway is required for morphologic and organizational changes in astrocytes that result in the formation and maintenance of the astrocytic tunnels. Through this neuron-glia interaction, the new neurons regulate the formation of the astrocytic meshwork that is needed to enable their rapid and directional migration in adult brain.
  • Musashi1 as a marker of reactive astrocytes after transient focal brain ischemia, Koichi Oki, Naoko Kaneko, Hiroaki Kanki, Takao Imai, Norihiro Suzuki, Kazunobu Sawamoto, Hideyuki Okano, NEUROSCIENCE RESEARCH, 66, (4) 390 - 395,   2010年04月, 査読有り, The synthesis of glial-fibrillary acidic protein (GFAP) or the re-expression of progenitor markers such as Nestin increases in reactive astrocytes after brain ischemia. We investigated the dynamics of reactive astrocytes after transient focal brain ischemia by examining the expression of Musashi1 (Msi1), an RNA-binding protein and another marker of neural stem/progenitor cells. In ischemic striatum induced by middle cerebral artery occlusion (MCAO), an increase in Msi1-immunoreactivity was observed from 2 days after MCAO, persisting until 14 days. The proliferation of Msi1-positive cells was observed from 4 days after MCAO and reached a peak at 7 days. These Msi1-positive cells were regarded as reactive astrocytes based on their co-expression with GFAP or Nestin and their morphology. Msi1-positive cells were located in the pen-infarct area in a region similar, but not identical, to that of Nestin-positive cells. The Msi1(+)Nestin(+) cells were located much closer to the ischemic core than the Msi1(+)Nestin(-) cells. The present study revealed that Msi1-expression, similar to Nestin, is induced after brain ischemia and may be involved in the reactivation of astrocytes, including their proliferation. However, the difference in the distributions of Msi1 and Nestin suggests that some of their features may differ in reactive astrocytes. (C) 2009 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
  • Roles of mDia isoforms, a Rho effector, in neural development, Ryota Shinohara, Dean Thumkeo, Hiroshi Kamijo, Naoko Kaneko, Kazunobu Sawamoto, Hiroyuki Hioki, Takeshi Kaneko, Keisuke Watanabe, Hirohide Takebayashi, Toshimasa Ishizaki, Tomoyuki Furuyashiki, Shuh Narumiya, NEUROSCIENCE RESEARCH, 68, E138 - E138,   2010年, 査読有り
  • New neurons form and maintain their path of astrocytic processes for rapid migration in the adult brain, Naoko Kaneko, Oscar Marin, Masato Koike, Yuki Hirota, Yasuo Uchiyama, Jane Y. Wu, Qiang Lu, Marc Tessier-Lavigne, Arturo Alvarez-Buylla, Hideyuki Okano, John L. R. Rubenstein, Kazunobu Sawamoto, NEUROSCIENCE RESEARCH, 68, E93 - E93,   2010年
  • Roles of disrupted-in-schizophrenia 1-interacting protein girdin in postnatal development of the dentate gyrus., Enomoto A, Asai N, Namba T, Wang Y, Kato T, Tanaka M, Tatsumi H, Taya S, Tsuboi D, Kuroda K, Kaneko N, Sawamoto K, Miyamoto R, Jijiwa M, Murakumo Y, Sokabe M, Seki T, Kaibuchi K, Takahashi M, Neuron, 63, (6) 774 - 787,   2009年09月, 査読有り
  • Adult neurogenesis and its alteration under pathological conditions., Kaneko N, Sawamoto K, Neuroscience research, 63, (3) 155 - 164,   2009年03月, 査読有り, 招待有り
  • In vivo imaging of sensory input-dependent neurogenesis in the adult olfactory bulb, Masato Sawada, Naoko Kaneko, Hiroaki Wake, Hiroyuki Inada, Yasuko Kato, Yuchio Yanagawa, Kazuto Kobayashi, Tomomi Nemoto, Junichi Nabekura, Kazunobu Sawamoto, Neurosci. Res,   2009年
  • SLIT-ROBO SIGNALING REGULATES THE MIGRATION OF NEW NEURONS UNDER PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS, 岡野 栄之, JOURNAL OF PHYSIOLOGICAL SCIENCES, 59, 442 - 442,   2009年
  • [Adult neurogenesis in physiological and pathological conditions]., Kaneko N, Sawamoto K, Brain and nerve = Shinkei kenkyu no shinpo, 60, 319 - 328,   2008年04月, 招待有り
  • [Neuronal migration in the adult brain]., Kaneko N, Sawamoto K, Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology, 28, 63 - 68,   2008年04月, 招待有り
  • Cyclin-dependent kinase 5 is required for control of neuroblast migration in the postnatal subventricular zone, Yuki Hirota, Toshio Ohshima, Naoko Kaneko, Makiko Ikeda, Takuji Iwasato, Ashok B. Kulkarni, Katsuhiko Mikoshiba, Hideyuki Okano, Kazunobu Sawamoto, JOURNAL OF NEUROSCIENCE, 27, (47) 12829 - 12838,   2007年11月, 査読有り, At the lateral wall of the lateral ventricles in the adult rodent brain, neuroblasts form an extensive network of elongated cell aggregates called chains in the subventricular zone and migrate toward the olfactory bulb. The molecular mechanisms regulating this migration of neuroblasts are essentially unknown. Here, we report a novel role for cyclin-dependent kinase 5 (Cdk5), a neuronal protein kinase, in this process. Using in vitro and in vivo conditional knock-out experiments, we found that Cdk5 deletion impaired the chain formation, speed, directionality, and leading process extension of the neuroblasts in a cell-autonomous manner. These findings suggest that Cdk5 plays an important role in neuroblast migration in the postnatal subventricular zone.
  • [Neuronal migration in the adult brain]., Kaneko N, Sawamoto K, Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology, 27, 215 - 218,   2007年11月, 招待有り
  • Suppression of cell proliferation by interferon-alpha through interleukin-1 production in adult rat dentate gyrus, Naoko Kaneko, Koutaro Kudo, Tadashi Mabuchi, Keiko Takemoto, Koichiro Fujimaki, Henny Wati, Hironobu Iguchi, Hideo Tezuka, Shigenobu Kanba, NEUROPSYCHOPHARMACOLOGY, 31, (12) 2619 - 2626,   2006年12月, 査読有り, The therapeutic use of interferon-alpha (IFN-alpha), a proinflammatory cytokine, is known to cause various neuropsychiatric adverse effects. In particular, depression occurs in 30-45% of patients, frequently interrupting treatment. IFN-alpha-treated animals also show depression-like behaviors. However, mechanisms underlying the depression caused by IFN-a remain to be defined. Recently, a decrease in adult hippocampal neurogenesis was revealed as a possible neuropathological mechanism of depression. Therefore, we investigated the effect of subchronic IFN-alpha treatment on neurogenesis in the adult rat dentate gyrus (DG). Immediately after the administration of IFN-alpha for 1 week, a decrease in the number of 5-bromo-deoxyuridine-labeled proliferating cells was observed in the DG; however, no effect was detected on the expression of mature neuronal phenotype in the newly formed cells 3 weeks later. Also, an increase in the level of interleukin-1beta (IL-1 beta), a major proinflammatory cytokine, was observed in the hippocampus following the administration of IFN-alpha. Furthermore, coadministration of an IL-1 receptor antagonist completely blocked the IFN-alpha-induced suppression of the cell-proliferative activity in the DG. Our results indicate that IFN-alpha suppresses neurogenesis in the DG, and that IL-1 beta plays an essential role in the suppression. The decreased cell proliferation caused by IFN-alpha-induced IL-1 beta may be responsible, at least in part, for IFN-alpha-induced depression.
  • Role of the cholinergic system in regulating survival of newborn neurons in the adult mouse dentate gyrus and olfactory bulb, Naoko Kaneko, Hideyuki Okano, Kazunobu Sawamoto, GENES TO CELLS, 11, (10) 1145 - 1159,   2006年10月, 査読有り, Neurogenesis in the subgranular zone of the hippocampal dentate gyrus and olfactory bulbs continues into adulthood and has been implicated in the cognitive function of the adult brain. The basal forebrain cholinergic system has been suggested to play a role in regulating neurogenesis as well as learning and memory in these regions. Herein, we report that highly polysialylated neural cell adhesion molecule (PSA-NCAM)-positive immature cells as well as neuronal nuclei (NeuN)-positive mature neurons in the dentate gyrus and olfactory bulb express multiple acetylcholine receptor subunits and make contact with cholinergic fibers. To examine the function of acetylcholine in neurogenesis, we used donepezil (Aricept), a potent and selective acetylcholinesterase inhibitor that improves cognitive impairment in Alzheimer's disease. Intraperitoneal administrations of donepezil significantly enhanced the survival of newborn neurons, but not proliferation of neural progenitor cells in the subgranular zone or the subventricular zone of normal mice. Moreover, donepezil treatment reversed the chronic stress-induced decrease in neurogenesis. Taken together, these results suggest that activation of the cholinergic system promotes survival of newborn neurons in the adult dentate gyrus and olfactory bulb under both normal and stressed conditions.
  • [Bipolar I disorder]., Kaneko N, Shioe K, Kanba S, Ryoikibetsu shokogun shirizu, 38, 251 - 255,   2003年

MISC

  • 内在性のニューロン再生過程における新生ニューロンの移動制御機構, 齋藤志朗, 金子奈穂子, 澤本和延, 生体の科学, 70, (1) 63 - 67,   2019年02月, 招待有り
  • エリスロポエチン派生物質による脳の修復と保護, 加古英介, 金子奈穂子, 祖父江和哉, 澤本和延, NAGOYA MEDICAL JOURNAL, 55, (3) 129 - 135,   2017年, 査読有り
  • Adult neural stem cells, Sawamoto K, Kaneko N, Nihon Rinsho, 73,   2015年06月
  • スリット1,2ダブルノックアウトマウスにおけるGnRHニューロンの移動と軸索投射, 村上 志津子, 金子 奈穂子, 澤本 和延, 内山 安男, 順天堂醫事雑誌, 59, (6) 532 - 532,   2013年12月
  • 精神疾患と海馬のニューロン新生, 藤岡哲平, 金子奈穂子, 澤本和延, Clinical Neuroscience, 31, (13年) 1446 - 1448,   2013年, 招待有り
  • 感覚入力による成体嗅球新生ニューロンの位置決定, 澤田雅人, 金子奈穂子, 稲田浩之, 和氣弘明, 加藤康子, 柳川右千夫, 小林和人, 根本知己, 鍋倉淳一, 澤本和延, Nagoya Med J, 52,   2012年02月01日
  • グリアとの相互作用による新生ニューロンの移動制御と傷害脳の再生過程の解析, 金子 奈穂子, Marin Oscar, 小池 正人, 廣田 ゆき, 内山 安男, Wu Jane Y, Lu Qiang, Tessier-Lavigne Marc, Alvarez-Buylla Arturo, 岡野 栄之, Rubenstein John L.R, 澤本 和延, Nagoya Medical Journal, 51, (4) 218 - 219,   2011年03月
  • グリアとの相互作用による新生ニューロンの移動制御と傷害脳の再生過程の解析, 金子 奈穂子, Marin Oscar, 小池 正人, 廣田 ゆき, 内山 安男, Wu Jane Y, Lu Qiang, Tessier-Lavigne Marc, Alvarez-Buylla Arturo, 岡野 栄之, Rubenstein John L.R, 澤本 和延, Nagoya Medical Journal, 51, (2) 130 - 130,   2010年09月
  • アストロサイトとの相互作用による新生ニューロン移動経路の形成・維持機構(New neurons form and maintain their path of astrocytic processes for rapid migration in the adult brain), 金子 奈穂子, Mari Oscar, 小池 正人, 廣田 ゆき, 内山 安男, Wu Jane Y, Lu Qiang, Tessier-Lavigne Marc, Alvarez-Buylla Arturo, 岡野 栄之, Rubenstein John L.R, 澤本 和延, 神経化学, 49, (2-3) 504 - 504,   2010年08月
  • 海馬ニューロンの新生と精神神経疾患 (特集 中枢神経の可塑性), 金子奈穂子, 澤本和延, 総合リハビリテ-ション, 38, (2) 114 - 120,   2010年02月
  • 細胞移植を用いない脳死間再生医療の可能性, 加古英介, 金子奈穂子, 祖父江和哉, 澤本和延, 生物物理化学, 53, (4) 103 - 107,   2009年12月, 招待有り
  • 成体脳におけるニューロン新生と脳梗塞後の神経新生メカニズム, 金子奈穂子, 澤本和延, 実験医学 増刊, 26, (12) 224 - 229,   2008年12月, 招待有り
  • 成体脳におけるニューロンの新生と移動・成熟, 金子奈穂子, 澤本和延, 日本神経精神薬理学雑誌 = Japanese journal of psychopharmacology, 28, (2) 63 - 68,   2008年04月25日
  • 成体脳のニューロン新生とその異常 (特集 神経系の発生とその異常), 金子奈穂子, 澤本和延, Brain and nerve, 60, (4) 319 - 328,   2008年04月
  • 成体脳における神経細胞の移動, 金子奈穂子, 澤本和延, 日本神経精神薬理学雑誌 = Japanese journal of psychopharmacology, 27, (5) 215 - 218,   2007年11月25日
  • 成体脳室下帯の神経発生・再生学, 廣田ゆき, 金子奈穂子, 澤本和延, 小児の脳神経 = Nervous System in Children, 31, (6) 428 - 431,   2006年12月31日
  • 成体脳内の神経細胞移動メカニズム, 金子奈穂子, 澤本和延, Medical Science Digest, 32, (14) 592 - 593,   2006年12月, 招待有り
  • 成体の脳で生まれ、移動する神経細胞, 金子奈穂子, 澤本和延, Bionics, 3, (6) 66 - 67,   2006年06月, 招待有り

講演・口頭発表等

  • インターフェロン療法中のうつ病発症と海馬のニューロン新生の変化, 金子 奈穂子, 第57 回日本神経化学会,   2014年10月01日, 招待あり
  • New neurons express Slit1 for their efficient migration through activated astrocytes in stroke-injured brain, 金子 奈穂子, 澤本 和延, 第37回日本神経科学大会,   2014年09月12日
  • アストロサイトによる脳傷害部への新生ニューロンの移動制御, 金子 奈穂子, 第87回日本薬理学会年会,   2014年03月19日, 招待あり
  • New neurons regulate Robo signaling in activated astrocytes to clear the path for their migration in the injured striatum after ischemic stroke., 金子 奈穂子, 澤本 和延, Neuro2013,   2013年06月22日
  • Impaired hippocampal neurogenesis and depressive behaviors in interferon-alpha-treated mice and monkeys,   2012年10月01日
  • Sensory input-dependent spatiotemporal regulation of neuronal turnover in the adult olfactory bulb glomeruli.,   2012年10月
  • New neurons migrate through the activated astrocytes in the brain after stroke using Slit-Robo signaling.,   2012年09月18日
  • 成体脳内を移動する新生ニューロンによるアストロサイトの形態制御, 金子 奈穂子, 澤本 和延, 第117回日本解剖学会総会・全国学術集会,   2012年03月26日, 招待あり
  • New neurons use Slit1 to maintain astrocytic tunnels for their rapid migration in the adult brain., Neuroscience 2011,   2011年11月16日
  • 霊長類脳の内在性神経幹細胞によるニューロンの再生, 金子 奈穂子, 第20回日本意識障害学会,   2011年09月20日, 招待あり
  • New neurons in the injured brain actively interact with activated astrocytes to migrate efficiently toward the injured area.,   2011年09月16日
  • アストロサイトとの相互作用による新生ニューロン移動経路の形成・維持機構, 金子 奈穂子, 第9回成体脳のニューロン新生懇談会,   2010年11月27日, 招待あり

受賞

  •   2019年07月, 日本神経化学会, 日本神経化学会優秀賞, 脳梗塞後のニューロン再生過程の解析
  •   2017年02月, 成体脳のニューロン新生懇談会, 優秀演題賞, 再生のポイントは新生ニューロンの移動>数!
  •   2013年07月, 日本炎症・再生医学会, 優秀演題賞, 虚血性脳傷害部位への新生ニューロンの移動における 活性化アストロサイトとの相互作用とその制御機構
  •   2010年12月, 名古屋市立大学 医学会, 名古屋市立大学医学会賞, 成体脳におけるニューロンーグリア相互作用と新生ニューロンの移動制御機構
  •   2010年03月, 日本再生医療学会, Young Investigator's Award 最優秀賞, グリア細胞との相互作用による新生ニューロンの移動制御機構

競争的資金

  • 最先端形態学・シングルセル遺伝子発現解析による生後脳のニューロン移動機構の解明, 日本学術振興会, 科学研究費助成事業 国際共同研究加速基金(国際共同研究強化(B)),   2018年10月09日 - 2021年03月31日, 生後の脳において神経幹細胞から生まれる新生ニューロンは、脳機能の維持および脳傷害後の神経再生・機能回復に関わっている。我々はこれまでに、様々なモデル動物を用いて、正常脳および傷害脳における新生ニューロンの移動メカニズムおよび周囲の細胞との相互作用を明らかにしてきた。本課題は、海外の研究室と共同で、移動する新生ニューロンと周囲の細胞の接着および細胞形態変化のメカニズムと、その意義を明らかにすることを目的としている。さらに、応募者の研究室に所属する若手研究者を参画させ、国際的に活躍できる研究者として養成する。本年度は、以下の研究を実施した。 (1)新生ニューロンの構造の解析:脳内を移動するニューロンの微細構造や他の細胞との関係について、名古屋市立大学および海外の研究機関で解析を行った。(2)傷害脳における新生ニューロンと血管の接着の解析:我々はこれまでに、ニューロンが血管を足場にして移動することを明らかにしてきた。ニューロンと足場としての血管の相互作用の詳細を理解するため、その微細構造等について海外の研究機関と共同で解析した。(3) 神経幹細胞の分化・移動調節因子の解析:新生ニューロンの移動・分化の分子メカニズムを明らかにするため、新生ニューロンの移動や分化調節に関わる遺伝子について、名古屋市立大学および海外の研究機関で解析を行った。 本研究の成果は、脳可塑性の未知のメカニズムの解明と、新たな神経再生技術の提供につながる可能性がある。
  • 新生ニューロンの移動制御による脳梗塞後の神経回路・機能再生の促進, 日本学術振興会, 科学研究費助成事業 基盤研究(C),   2017年04月01日 - 2020年03月31日, 成熟後の脳でも、脳室下帯では神経幹細胞が維持されて、ニューロンが持続的に産生されている。我々はこれまでの研究により、脳室下帯で産生された新生ニューロンが、Slit-Roboシグナルを介して脳梗塞で活性化したアストロサイトの形態を制御して、脳梗塞巣へ向かう移動経路を維持していることを明らかにした。レンチウィルスベクターを用いて新生ニューロンにSlit1の持続発現を誘導すると、新生ニューロンの脳梗塞巣への移動が促進された。このベクターを導入して、脳梗塞モデルマウスの脳内に移植すると、脳梗塞後の運動機能の改善が促進され、効果は長期的に維持された。そこで、本年度は、これらのマウスにおける運動機能改善の神経学的基盤を明らかにするため、組織学的解析を行った。 Slit1発現を増強した新生ニューロンの線条体ニューロンへの分化、シナプス形成、軸索の分布を、免疫染色法によって解析した。線条体の投射性ニューロン・介在ニューロンのマーカーを発現する細胞の割合を対照群と比較したところ、有意な差は見られなかった。また、梗塞巣内に移植した細胞は、Slit1発現群・対照群ともにほとんどの細胞がアストロサイトに分化し、成熟ニューロンへの分化は見られなかった。次に、線条体投射ニューロンの投射先のひとつである淡蒼球において移植細胞由来ニューロンの軸索の分布を解析した。対照群では軸索が淡蒼球内側のみに集中していたがSlit発現群では淡蒼球内広範囲に分布していた。また、運動機能の改善度は、梗塞巣に近い領域で成熟ニューロンに分化した細胞の割合と見られた。これらの結果から、新生ニューロンの移動を促進し、定着位置を制御することによって、効率的に神経回路の再生が誘導されることが示唆された。
  • 傷害脳内を移動する新生ニューロンと活性化アストロサイトのクロストーク, 文部科学省, 科学研究費補助金(新学術領域研究(研究領域提案型)),   2013年 - 2014年
  • 脳梗塞後のニューロン再生過程における新生ニューロン-アストロサイト相互作用の解析, 文部科学省, 科学研究費補助金(若手研究(A)),   2011年 - 2014年, 1.Slit発現による新生ニューロンの移動促進と脳梗塞後の再生過程の解析:新生ニューロン自身が発現するSlit1の役割を明確にするため、脳梗塞術後の野生型マウス脳にSlit1欠損または野生型新生ニューロンを移植し、移動を比較した。野生型新生ニューロンは、移植部から梗塞巣に向けて広く分布したが、Slit1欠損新生ニューロンの大部分は移植部付近に留まり、周囲のアストロサイトとの接触にも異常がみられた。2.移動する新生ニューロンと活性化アストロサイトの接触部の微細構造の解析: Slit1欠損マウス・野生型マウス脳梗塞モデルを作製し、H.24年3月より(3ヶ月間)バレンシア大学Garcia-Verdugo研究室にて、傷害部へ移動する新生ニューロンの移動形態・アストロサイトとの接触の電子顕微鏡解析を開始した。3.低酸素曝露後のアストロサイトのRobo発現・局在変化の解析:脳室下帯のアストロサイトが成体でも増殖を続けているのに対し、線条体アストロサイトは生理的条件下ではほとんど増殖しない。線条体アストロサイトを活性化するため低酸素に20時間曝露し、その後のRobo発現の変化をreal-time PCRを用いて経時的に解析した。低酸素曝露によって、急激なGFAP発現の上昇に続いて3日後からRobo2の発現が増加することが分かった。4.新生ニューロンによる活性化アストロサイトの形態制御メカニズムの解析:アストロサイトが新生ニューロンと接触したときの細胞内骨格系の変化を解析するため、脳室下帯アストロサイトを用いてイメージング手法を検討し、予備的データを得た。アクチン重合を可視化する分子を電気穿孔法にて導入したアストロサイトと新生ニューロンを共培養し、レーザー顕微鏡でタイムラプス撮影を行った。移動する新生ニューロンとの接触面で、局所的にアストロサイトのアクチン重合が低下する可能性が示唆された。
  • 正常脳・傷害脳のニューロブラストの移動におけるSlitの機能の解析, 文部科学省, 科学研究費補助金(若手研究(B)),   2008年 - 2010年, 成体脳の脳室下帯で産生された新生ニューロンは、非侵襲時には嗅球へ、また脳傷害時には傷害部に移動し成熟する。このとき新生ニューロンは、アストロサイトが密生した経路を高速で移動するが、その相互作用メカニズムは不明であった。我々は本研究で、成体脳を移動する新生ニューロンが分泌性タンパク質Slit1 の発現により、移動経路に密生しているアストロサイトの形態・分布を制御し、自身の高速移動を可能にする移動経路の形成・維持を行っていることを明らかにした。この機構は、傷害部への新生ニューロンの移動にも関与していることが示唆された。
  • 中枢神経疾患の再生機構
  • 成体脳におけるニューロンの移動機構


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