2002 Fiscal Year Annual Research Report

ニューロン・グリアの分化決定とニューロンの個性獲得にいたる制御機構の解析

Research Project

Project/Area Number	12210013
Research Institution	Keio University
Principal Investigator	岡野栄之慶應義塾大学, 医学部, 教授 (60160694)
Keywords	神経幹細胞 / 自己複製 / 分化調節機構 / Musashi / 水頭症 / neurosphere / アンチセンス / 生存維持
Research Abstract	本研究は、神経幹細胞の自己複製と分化調節機構を解析するため、神経幹細胞に強い発現のみられるRNA結合性蛋白質Musashi(Msi)ファミリーの機能解析を、遺伝子欠損マウスを用いて行った。Msiファミリー蛋白質は、哺乳類の神経幹細胞に強い発現のみられるRNA結合蛋白質として同定されてきた。このmsi1遺伝子を欠失したマウスを作成し解析を行ったところ、高頻度で先天性水頭症を発症して、生後約1-2ヶ月で死亡することが明らかとなった。詳細な組織学的解析によりこの水頭症は、中脳水道周囲に局在する神経幹細胞・前駆細胞の分化・増殖の制御異常によって引き起こされる閉塞性水頭症であることが明らかとなった。また、胎児期のマウス線条体から採取した神経幹細胞は、EGF・bFGF存在下で培養すると分裂をくり返して細胞塊(Neurosphere)を形成するが、msi1遺伝子欠損マウスにおいてはこのNeuroshpere形成能に異常は認められないものの、msi1遺伝子欠損マウスに対してmsi2の発現を阻害するアンチセンスオリゴを導入したところ、Neurosphere形成能が低下した。このことから、msi1とmsi2は協調して神経幹細胞の維持や増殖に重要な役割を担っていると考えられた。更に、Msi1と類似した構造を持つMsi2の解析を行いMsiファミリー蛋白質の協調的な働きを明らかにするために、msi2遺伝子欠損マウスを作成し、交配によってmsi1およびmsi2遺伝子の二重欠損マウスを作成したところ、より高率に、より早期から先天性水頭症の原因となる組織異常が出現することが明らかになった。Msi1とMsi2の両蛋白質が、ともに神経幹細胞の増殖や分化の制御に強く関与していることが本研究によって明らかになった。

Research Products

(26 results)

All Other

All Publications (26 results)

[Publications] Iwai Y, Hirota Y, Ozaki K, Okano H, Takeichi M, Uemura T: "DN-cadherin-dependent synaptogenesis in the Drosophila visual system"Mol Cell Neurosci. 19. 375-388 (2002)
[Publications] Takasawa K-I, Kitagawa K, Yagita Y, Sasaki T, Tanaka S, Ohtsuki T, Miyata T, Okano H, Hori M, Matsumoto M: "Increased proliferation of neural progenitor cells but reduced survival newborn cells in the contralateral hippocampus after focal cerebral ischemia in rats"J Cerebral Blood Flow and Metabolism. 22. 299-307 (2002)
[Publications] Shibata M, Yamawaki T, Fukuuchi Y, Okano H, Miura M: "Up-regulation of Akt Phosphorylation Contributes to Improved Cell Viability in the Ischemic Penumbra at the Early Stage of Middle Cerebral Artery Occlusion in Mice"Brain Res. 942. 1-10 (2002)
[Publications] Shu H-J, Saito T, Watanabe H, Ito J-I, Takeda H, Okano H, Kawata S: "Expression of the Musahi1 gene encoding the RNA-binding protein in human hepatoma cell lines"Biochem. Biophys. Res. Com. 293. 150-154 (2002)
[Publications] Cuadrado, A., Garcia-Fernandez, L.F., Imai, T., Okano, H., Munoz, A: "Neural RNA-binding protein Musashi-1 modulates tau pre-mRNA alternative splicing and is regulated by thyroid hormone in the developing rat brain"Mol.Cell.Neurosci.. 20. 98-210 (2002)
[Publications] Shamnloula, H.K., Mbogho, M.P., Pimentel, A.C., Chrzanowska-Lightowlers, Z.M.A., Hyatt, V., Okano, H., Venkatech, T.R: "rugose (rg), a Drosophila A kinase Anchor Protein (DAKAP), is required for retinal pattern formation and interacts genetically with multiple signaling pathways"Genetics. 161. 693-710 (2002)
[Publications] Yagita, Y., Kitagawa, K., Sasaki, T., Miyata, T., Okano, H., Hori, T., Matsumoto, M: "Musahi1 and Nestin as useful markers of neuronal progenitor cells in rat hippocampus after forebrain ischemia"J.Neurosci.Res. 69. 750-756 (2002)
[Publications] Ogawa, Y., Sawamoto, K., Miyata, T., Miyao, S., Watanabe, M., Toyama, Y., Nakamura, M., Bregman, B.S., Koike, M., Uchiyama, Y., Okano, H: "Transplantation of in vitro expanded fetal neural progenitor cells results in neurogenesis and functional recovery after spinal cord contusion injury in adult rats"J.Neurosci.Res. 69. 925-933 (2002)
[Publications] Murayama A, Matsuzaki Y, Kawaguti A, Shimazaki T, Okano H: "Flow cytometric analysis of stem cells in the developing and adult mouse brain"J.Neurosci.Res. 69. 837-847 (2002)
[Publications] Johansson CB, Lothian C, Molin M, Okano H, Lendahl U: "Nestin enhancer requirements for expression in normal and injured adult CNS"J.Neurosci.Res. 69. 784-794 (2002)
[Publications] Kanemura, Y., Mori, H., Kobayashi, S., Islam, O., Kodama E., Yamamoto, A., Nakanishi Y., Arita, N., Yamasaki, M., Okano, H., Miyake, J., Hara, M.: "Evaluation of in-vitro proliferative activity of human fetal neural stem cell"J.Neurosci.Res. 69. 869-879 (2002)
[Publications] Kuranaga, E., Kanuka, H., Igaki, T., Sawamoto, K., Ichijo, H., Okano, H., Miura, M: "Reaper-mediated inhibition of DIAP1-induced DTRAF1 degradation results in activation of JNK in Drosophila"Nat Cell Biol. 4. 705-710 (2002)
[Publications] Sakakibara, S., Nakamura, Y., Koike, M., Takano, H., Uchiyama, Y., Noda, T., Okano, H: "RNA-binding protein Musashi family, roles for CNS stem cells and a subpopulation of ependymal cells revealed by targeted disruption and antisense ablation"Proc.Natl.Acad.Sci.USA. 99. 15194-15199 (2002)
[Publications] Hirota Y., Sawamoto, K., Okano, H: "Tincar encodes a novel transmembrane protein expressed in the Tinman-expressing cardioblasts of Drosophila"Gene Expression Patterns. 2. 323-327 (2002)
[Publications] Okano, H., Yoshizaki, T., Shimazaki, T., Sawamoto, K: "Isolation and transplantation of Dopaminergic Neurons and Neural Stem Cells"Parkinson & Related Disorders. 9. 23-28 (2002)
[Publications] Okano, H., Imai, T., Okabe, M: "Musashi : a translational regulator of cell fates"J.Cell Sci. 115. 1355-1359 (2002)
[Publications] Okano, H: "The stem cell biology of the central nervous system"J.Neurosci.Res. 69. 698-707 (2002)
[Publications] Okano, H: "Neural stem cells : progression of basic research and perspective for clinical application"Keio J.Med. 51. 115-128 (2002)
[Publications] Potten, C.S., Booth C., Tudor, G.L., Booth, D., Brady, G., Hurley, P., Ashton, G., Clarke, G., Sakakibara, S., Okano, H.: "Identification of a putative intestinal stem cell marker and early lineage marker, Musashi1"Differentiation. 71. 28-41 (2003)
[Publications] Kayahara, T., Sawada, M., Takaishi, S., Fukui, H., Seno, H., Fukuzawa, H., Suzuki, K., Hiai, H., Kageyama, R., Okano, H., Chiba, T.: "Candidate markers for stem and early progenitor cells, Musashi-1 and Hes1, are expressed in crypt base columnar cells of mouse small intestine"FEBS Letter. 535. 131-135 (2003)
[Publications] Tonchev, A.B., Zhao, L., Yamashima, T., Okano, H: "Differential proliferative response in the postischemic hippocampus, temporal cortex and olfactory bulb of adult primates"Glia. (in press). (2003)
[Publications] Tonchev, A.B., Yamashima, T., Zhao, L., Okano, H.J., Okano, H: "Increased proliferation of neural progenitors and neurogenesis in the postischemic brain of young adult primates"Mol.Cell.Neurosci. (in press). (2003)
[Publications] Sasaki, T., Kitagawa, K., Sugimura, S., Omura-Matsuoka, E., Tanaka, S., Yagita, Y., Okano, H: "Matsumoto, M. and Hori, M. : Implication of Cyclooxygenase-2 on enhanced neurogenesis in the adult hippocampus after ischemia"J.Neurosci.Res. (in press). (2003)
[Publications] Nakamura, Y., Yamamoto, M., Oda, E., Yamamoto, A., Kanemura, Y., Hara, M., Suzuki, A., Yamasaki, M., Okano, H: "Expression of tubulin beta II in neural stem/progenitor cells and radial fibers during human fetal brain development"Lab Invest. (in press). (2003)
[Publications] Okano, H., Ogawa, Y., Nakamura, M., Kaneko, S., Iwanami, A., Toyama, A.: "Transplantation of neural stem cells into the spinal cord after injury"Seminar in Cell & Developmental Biol. (in press). (2003)
[Publications] Sawamoto K, Okano H: "Recent Res.Devel.Mol.Cell Biol."Research Signpost. 661 (2002)

2002 Fiscal Year Annual Research Report

ニューロン・グリアの分化決定とニューロンの個性獲得にいたる制御機構の解析

Principal Investigator

岡野 栄之 慶應義塾大学, 医学部, 教授 (60160694)

Research Products

[Publications] Iwai Y, Hirota Y, Ozaki K, Okano H, Takeichi M, Uemura T: "DN-cadherin-dependent synaptogenesis in the Drosophila visual system"Mol Cell Neurosci. 19. 375-388 (2002)

[Publications] Shibata M, Yamawaki T, Fukuuchi Y, Okano H, Miura M: "Up-regulation of Akt Phosphorylation Contributes to Improved Cell Viability in the Ischemic Penumbra at the Early Stage of Middle Cerebral Artery Occlusion in Mice"Brain Res. 942. 1-10 (2002)

[Publications] Shu H-J, Saito T, Watanabe H, Ito J-I, Takeda H, Okano H, Kawata S: "Expression of the Musahi1 gene encoding the RNA-binding protein in human hepatoma cell lines"Biochem. Biophys. Res. Com. 293. 150-154 (2002)

[Publications] Cuadrado, A., Garcia-Fernandez, L.F., Imai, T., Okano, H., Munoz, A: "Neural RNA-binding protein Musashi-1 modulates tau pre-mRNA alternative splicing and is regulated by thyroid hormone in the developing rat brain"Mol.Cell.Neurosci.. 20. 98-210 (2002)

[Publications] Yagita, Y., Kitagawa, K., Sasaki, T., Miyata, T., Okano, H., Hori, T., Matsumoto, M: "Musahi1 and Nestin as useful markers of neuronal progenitor cells in rat hippocampus after forebrain ischemia"J.Neurosci.Res. 69. 750-756 (2002)

[Publications] Murayama A, Matsuzaki Y, Kawaguti A, Shimazaki T, Okano H: "Flow cytometric analysis of stem cells in the developing and adult mouse brain"J.Neurosci.Res. 69. 837-847 (2002)

[Publications] Johansson CB, Lothian C, Molin M, Okano H, Lendahl U: "Nestin enhancer requirements for expression in normal and injured adult CNS"J.Neurosci.Res. 69. 784-794 (2002)

[Publications] Kanemura, Y., Mori, H., Kobayashi, S., Islam, O., Kodama E., Yamamoto, A., Nakanishi Y., Arita, N., Yamasaki, M., Okano, H., Miyake, J., Hara, M.: "Evaluation of in-vitro proliferative activity of human fetal neural stem cell"J.Neurosci.Res. 69. 869-879 (2002)

[Publications] Kuranaga, E., Kanuka, H., Igaki, T., Sawamoto, K., Ichijo, H., Okano, H., Miura, M: "Reaper-mediated inhibition of DIAP1-induced DTRAF1 degradation results in activation of JNK in Drosophila"Nat Cell Biol. 4. 705-710 (2002)

[Publications] Hirota Y., Sawamoto, K., Okano, H: "Tincar encodes a novel transmembrane protein expressed in the Tinman-expressing cardioblasts of Drosophila"Gene Expression Patterns. 2. 323-327 (2002)

[Publications] Okano, H., Yoshizaki, T., Shimazaki, T., Sawamoto, K: "Isolation and transplantation of Dopaminergic Neurons and Neural Stem Cells"Parkinson & Related Disorders. 9. 23-28 (2002)

[Publications] Okano, H., Imai, T., Okabe, M: "Musashi : a translational regulator of cell fates"J.Cell Sci. 115. 1355-1359 (2002)

[Publications] Okano, H: "The stem cell biology of the central nervous system"J.Neurosci.Res. 69. 698-707 (2002)

[Publications] Okano, H: "Neural stem cells : progression of basic research and perspective for clinical application"Keio J.Med. 51. 115-128 (2002)

[Publications] Potten, C.S., Booth C., Tudor, G.L., Booth, D., Brady, G., Hurley, P., Ashton, G., Clarke, G., Sakakibara, S., Okano, H.: "Identification of a putative intestinal stem cell marker and early lineage marker, Musashi1"Differentiation. 71. 28-41 (2003)

[Publications] Tonchev, A.B., Zhao, L., Yamashima, T., Okano, H: "Differential proliferative response in the postischemic hippocampus, temporal cortex and olfactory bulb of adult primates"Glia. (in press). (2003)

[Publications] Tonchev, A.B., Yamashima, T., Zhao, L., Okano, H.J., Okano, H: "Increased proliferation of neural progenitors and neurogenesis in the postischemic brain of young adult primates"Mol.Cell.Neurosci. (in press). (2003)

[Publications] Sasaki, T., Kitagawa, K., Sugimura, S., Omura-Matsuoka, E., Tanaka, S., Yagita, Y., Okano, H: "Matsumoto, M. and Hori, M. : Implication of Cyclooxygenase-2 on enhanced neurogenesis in the adult hippocampus after ischemia"J.Neurosci.Res. (in press). (2003)

[Publications] Nakamura, Y., Yamamoto, M., Oda, E., Yamamoto, A., Kanemura, Y., Hara, M., Suzuki, A., Yamasaki, M., Okano, H: "Expression of tubulin beta II in neural stem/progenitor cells and radial fibers during human fetal brain development"Lab Invest. (in press). (2003)

[Publications] Okano, H., Ogawa, Y., Nakamura, M., Kaneko, S., Iwanami, A., Toyama, A.: "Transplantation of neural stem cells into the spinal cord after injury"Seminar in Cell & Developmental Biol. (in press). (2003)

[Publications] Sawamoto K, Okano H: "Recent Res.Devel.Mol.Cell Biol."Research Signpost. 661 (2002)

岡野栄之慶應義塾大学, 医学部, 教授 (60160694)