2001 年度実績報告書

中枢神経系幹細胞の分化機構の解析

研究課題

研究課題/領域番号	12308042
研究機関	慶應義塾大学
研究代表者	岡野栄之慶應義塾大学, 医学部, 教授 (60160694)
キーワード	gp130 / 神経幹細胞 / EGFのレセプター / Gab1 / 欠失変異体マウス / 長期維持機構 / オリゴデンドロサイト前駆細胞 / GFAP
研究概要	本研究では、このgp130、そして神経幹細胞のmitogenであるEGFのレセプターの下流で働くシグナル伝達分子であり、MAP kinase経路の活性化に関与しているGab1の欠失変異体マウスにおける神経幹細胞の動態を含めた中枢神経系発生の異常を解析することによって、神経幹細胞の長期維持機構およびの本質に更にせまることを目的としている。 Gab1のホモ欠失変異体(gab^<-/->)は胎生16日目までに胎盤の発達異常により死亡してしまう故に、まず、胎生14目目の線条体における神経幹細胞の数をneurosphere法によって野生型と比較したところ、顕著な差は見られなかったが、EGFに対する反応性は消失していた。また、この時期に現れ始めるオリゴデンドロサイト前駆細胞の数が減少していた。しかしながら、ニューロンの分化および生存に変化は見られなかった。さらに、ヘテロ欠失変異体(gab^<+/->)の成体の側脳室周囲に存在している神経幹細胞の数を、これもneurosphere法によって調べたところ、野生型に比べて約80%その数が増加していた。また、gp130を介したシグナルによってその発現が亢進されるGFAPの発現は生後7日目の脊髄および成体脳でも低下していた。一方、これまでubiquitousに発現すると考えられていたGab1の中枢神経系の発生過程における発現を組織免疫化学染色によって確かめたところ、驚いたことに神経幹細胞が最も多く存在すると考えられる脳室周囲での発現が、生後2日目までは非常に低く、それ以外の領域で強く発現していた。しかしながら、生後19日目および成体においては脳室周囲に強く発現していた。これらのことは、Gab1が主に生後から成体に至るまでの神経幹細胞の維持に負に作用しており、胎生期では主にオリゴデンドロサイト前駆細胞の分化増殖あるいは生存に必要であることを示唆している。

研究成果

(25件)

すべてその他

すべて文献書誌 (25件)

[文献書誌] Toda M, Iizuka Y, Yu W-J, Ikeda E, Yoshida K, Imai T, Kawase T, Kawakami Y, Okano H, Uyemura K: "Expression of the neural RNA-binding protein Musashi1 in human gliomas"Glia. 34. 1-7 (2001)
[文献書誌] Mori H, Sakakibara S, Imai T, Nakamura Y, Iijima T, Suzuki A, Yuasa Y, Takeda M, Okano H: "Expression of mouse igf2 mRNA-binding protein 3 and its implication in the developing central nervous system"J Neurosci Res. 64. 132-143 (2001)
[文献書誌] Murata T, Nagaso H, Watanabe S, Okano H, Yokoyama K: "The hiiragi gene encodes a poly(A) polymerase, which controls the formation of the wing margin in Drosophila melanogaster"Dev Biol. 233. 137-147 (2001)
[文献書誌] Okabe M, Imai T, Kurusu M, Hiromi Y, Okano H: "Translational repression determines a neuronal potential in Drosophila asymmetric cell division"Nature. 41. 94-98 (2001)
[文献書誌] Sawamoto K, Yamamoto A, Kawagychi A, Yamaguchi M, Mori K, Goldman SA, Okano, H: "Visualization and direct isolation of neuronal progenitor cells by dual-color flow cytometric detection of fluorescent proteins"J Neurosci Res. 65. 220-227 (2001)
[文献書誌] Sawamoto K, Nakao N, Kakishita K, Ogawa Y, Toyama Y, Yamamoto A, Yamaguchi M, Mori K, Goldman SA, Itakura T, Okano H: "Generation of dopaminergic neurons in the adult brain from mesencephalic precursor cells labeled with a nestin-GFP transgene"J Neurosci. 21. 3895-3903 (2001)
[文献書誌] Imai T, Tokunaga A, Yoshida T, Hashimoto M, Weinmaster G, Mikoshiba K, Nakafuku M, Okano H: "The neural RNA-binding protein Musashi1 translationally regulaties the m-numb gene expression by interacting with its mRNA"Mol Cell Biol. 21. 3888-3900 (2001)
[文献書誌] Sawamoto K, Nakao N, Kobayashi K, Matsushita N, Takahashi H, Kakishita K, Yamamoto A, Yoshizaki T, Terashima T, Murakami F, Itakura T, Okano H: "Visualization and direct isolation of midbrain dopaminergic neurons expressing GFP"Proc Natl Acad Sci USA. 98. 6423-6423 (2001)
[文献書誌] Uchida M, Hanai S, Uematsu N, Sawamoto K, Okano H, Miwa M, Uchida K: "Genetic and functional analysis of PARP, a DNA strand break-binding enzyme"Mutat Res. 47. 89-96 (2001)
[文献書誌] Ishida Y, Nakamoto H, Imai H, Suzuki S, Okano H, Suzuki H: "Heme oxygenase-1 regulates vascular tone of the peritoneum undergoing peritoneal dialysis"Advances in Peritoneal Dialysis. 17. 15-19 (2001)
[文献書誌] Li R-Y, Baba S, Kosugi I, Arai Y, Kawasaki H, Shinmura Y, Sakakibara S, Okano H, Tsusui Y: "Activation of murine cytomegalovirus immediate-early promoter in cerebral ventricular zone and glial progenitor cells in transgenic mice"Gila. 35. 41-52 (2001)
[文献書誌] Yagita Y, Kitagawa K, Otsuki T, Kuwabara K, Mabuchi T, Miyata T, Okano H, Hori M, Matsumoto, M: "Proliferation of neuronal progenitor cells and increased neurogenesis in the ischemic adult rat hippocampus"Stroke. 32. 1890-1896 (2001)
[文献書誌] Miyata T, Kawaguchi A, Okano H, Ogawa M: "Asymmetric inheritance of radial glial fibers to neurons during corticogensis in mice"Neuron. 31. 727-741 (2001)
[文献書誌] Kahyama J, Abe H, Shimazaki T, Koizumi A, Nakashima K, Taga T, Okano H, Hata J, Umezawa A: "Brain from Bone : Efficient "meta-differentiation" of marrow stromalderived mature osteoblasts to neurons with Noggin or a demethylating agant"Differentiation. 68. 235-244 (2001)
[文献書誌] Keyoung H.M, Roy N.S, Benraiss A, Louissaint A Jr, Suzuki A, Hashimoto K, Rashbaum WK, Okano H, Goldman SA: "Prospective identification, selection and extraction of two distinct pools of neural stem cells fetal human brain"Nature Biotech. 19. 843-850 (2001)
[文献書誌] Kanemura Y, Mori K, Sakakibara S, Ohnishi T, Fujikawa H, Hayashi, H., Matsumoto T, Imai T, Ohnishi T, Fushiki S, Nakamura Y, Yamasaki M, Okano H, Arita N: "Musashi1, an evolutionarily conserved neural RNA-binding protein is a versatile marker of human glioma cells in determining their cellluar origin, malignancy and proliferative activity"Differentiation. 68. 141-152 (2001)
[文献書誌] Sakakibara S, Nakamura Y, Satoh H, Okano H: "RNA-binding protein Musashi2 : developmentally regulated expression in neural precursor cells and subpopulation of neurons in mammalian CNS"J Neurosci. 21. 8097-8107 (2001)
[文献書誌] Yamamoto N, Matsunaga E, Yamamoto S, Kobayashi D, Torii M, Kawaichi M, Kishi N, Matsuno K, Okano H, Nakafuku M: "Deltex as a nuclear signal transducer downstream of the Notch receptor"J Biol Chem. 276. 45031-45940 (2001)
[文献書誌] Saunders PTK, Maguire SM, Macpherson S, Fenelon MC, Sakakibara S, Okano H: "The RNA binding protein Musashi(Msi1)is expressed in the cytoplasm and nucleus of Sertoli cells in the rat testis from fetal life to adulthood"Biology of Reproduction. 66. 500-507 (2002)
[文献書誌] Uchida M, Hanai S, Uematsu N, Sawamoto K, Okano H, Miwa M, Uchida K: "Overexpression of poly(ADP-ribose) polymerase disrupts organization of cytoskeletal F-actin and tissue polarity in Drosophila"J Biol Chem. 277. 6696-6702 (2002)
[文献書誌] Matsumoto K, Ito M, Hori K, Miyashita F, Suzuki S, Kishi N, Artravanis-Tsakonas S, Okano H: "Involvement of a proline-rich motif and a RING-H2 finger in a function of Deltex as a regulator of Notch signaling"Development. 129. 1049-1059 (2002)
[文献書誌] Iwai Y, Hirota Y, Ozaki K, Okano H, Takeichi M, Uemura T: "DN-cadherin-dependent synaptogenesis in the Drosophila visual system"Mol Cell Neurosci. (in press). (2002)
[文献書誌] 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. (in press). (2002)
[文献書誌] Shibata M, Yamawaki T, Fukuuchi Y, Okano H, Miura M: "Up-reguration 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. (in press). 141-152 (2002)
[文献書誌] Okano H, Sakakibara S, Sawamoto K, Nakamura Y, Kaneko Y, Akamatsu W, Tokunaga A, Imai T, Miyata T, Shimazaki T: "5th International Symposium on Tissue Engineering for Therapeutic Use"Elsevier science B.V.. 226 (2001)

2001 年度 実績報告書

中枢神経系幹細胞の分化機構の解析

研究代表者

岡野 栄之 慶應義塾大学, 医学部, 教授 (60160694)

研究成果

[文献書誌] Toda M, Iizuka Y, Yu W-J, Ikeda E, Yoshida K, Imai T, Kawase T, Kawakami Y, Okano H, Uyemura K: "Expression of the neural RNA-binding protein Musashi1 in human gliomas"Glia. 34. 1-7 (2001)

[文献書誌] Mori H, Sakakibara S, Imai T, Nakamura Y, Iijima T, Suzuki A, Yuasa Y, Takeda M, Okano H: "Expression of mouse igf2 mRNA-binding protein 3 and its implication in the developing central nervous system"J Neurosci Res. 64. 132-143 (2001)

[文献書誌] Murata T, Nagaso H, Watanabe S, Okano H, Yokoyama K: "The hiiragi gene encodes a poly(A) polymerase, which controls the formation of the wing margin in Drosophila melanogaster"Dev Biol. 233. 137-147 (2001)

[文献書誌] Okabe M, Imai T, Kurusu M, Hiromi Y, Okano H: "Translational repression determines a neuronal potential in Drosophila asymmetric cell division"Nature. 41. 94-98 (2001)

[文献書誌] Sawamoto K, Yamamoto A, Kawagychi A, Yamaguchi M, Mori K, Goldman SA, Okano, H: "Visualization and direct isolation of neuronal progenitor cells by dual-color flow cytometric detection of fluorescent proteins"J Neurosci Res. 65. 220-227 (2001)

[文献書誌] Sawamoto K, Nakao N, Kakishita K, Ogawa Y, Toyama Y, Yamamoto A, Yamaguchi M, Mori K, Goldman SA, Itakura T, Okano H: "Generation of dopaminergic neurons in the adult brain from mesencephalic precursor cells labeled with a nestin-GFP transgene"J Neurosci. 21. 3895-3903 (2001)

[文献書誌] Imai T, Tokunaga A, Yoshida T, Hashimoto M, Weinmaster G, Mikoshiba K, Nakafuku M, Okano H: "The neural RNA-binding protein Musashi1 translationally regulaties the m-numb gene expression by interacting with its mRNA"Mol Cell Biol. 21. 3888-3900 (2001)

[文献書誌] Sawamoto K, Nakao N, Kobayashi K, Matsushita N, Takahashi H, Kakishita K, Yamamoto A, Yoshizaki T, Terashima T, Murakami F, Itakura T, Okano H: "Visualization and direct isolation of midbrain dopaminergic neurons expressing GFP"Proc Natl Acad Sci USA. 98. 6423-6423 (2001)

[文献書誌] Uchida M, Hanai S, Uematsu N, Sawamoto K, Okano H, Miwa M, Uchida K: "Genetic and functional analysis of PARP, a DNA strand break-binding enzyme"Mutat Res. 47. 89-96 (2001)

[文献書誌] Ishida Y, Nakamoto H, Imai H, Suzuki S, Okano H, Suzuki H: "Heme oxygenase-1 regulates vascular tone of the peritoneum undergoing peritoneal dialysis"Advances in Peritoneal Dialysis. 17. 15-19 (2001)

[文献書誌] Li R-Y, Baba S, Kosugi I, Arai Y, Kawasaki H, Shinmura Y, Sakakibara S, Okano H, Tsusui Y: "Activation of murine cytomegalovirus immediate-early promoter in cerebral ventricular zone and glial progenitor cells in transgenic mice"Gila. 35. 41-52 (2001)

[文献書誌] Yagita Y, Kitagawa K, Otsuki T, Kuwabara K, Mabuchi T, Miyata T, Okano H, Hori M, Matsumoto, M: "Proliferation of neuronal progenitor cells and increased neurogenesis in the ischemic adult rat hippocampus"Stroke. 32. 1890-1896 (2001)

[文献書誌] Miyata T, Kawaguchi A, Okano H, Ogawa M: "Asymmetric inheritance of radial glial fibers to neurons during corticogensis in mice"Neuron. 31. 727-741 (2001)

[文献書誌] Kahyama J, Abe H, Shimazaki T, Koizumi A, Nakashima K, Taga T, Okano H, Hata J, Umezawa A: "Brain from Bone : Efficient "meta-differentiation" of marrow stromalderived mature osteoblasts to neurons with Noggin or a demethylating agant"Differentiation. 68. 235-244 (2001)

[文献書誌] Keyoung H.M, Roy N.S, Benraiss A, Louissaint A Jr, Suzuki A, Hashimoto K, Rashbaum WK, Okano H, Goldman SA: "Prospective identification, selection and extraction of two distinct pools of neural stem cells fetal human brain"Nature Biotech. 19. 843-850 (2001)

[文献書誌] Sakakibara S, Nakamura Y, Satoh H, Okano H: "RNA-binding protein Musashi2 : developmentally regulated expression in neural precursor cells and subpopulation of neurons in mammalian CNS"J Neurosci. 21. 8097-8107 (2001)

[文献書誌] Yamamoto N, Matsunaga E, Yamamoto S, Kobayashi D, Torii M, Kawaichi M, Kishi N, Matsuno K, Okano H, Nakafuku M: "Deltex as a nuclear signal transducer downstream of the Notch receptor"J Biol Chem. 276. 45031-45940 (2001)

[文献書誌] Saunders PTK, Maguire SM, Macpherson S, Fenelon MC, Sakakibara S, Okano H: "The RNA binding protein Musashi(Msi1)is expressed in the cytoplasm and nucleus of Sertoli cells in the rat testis from fetal life to adulthood"Biology of Reproduction. 66. 500-507 (2002)

[文献書誌] Uchida M, Hanai S, Uematsu N, Sawamoto K, Okano H, Miwa M, Uchida K: "Overexpression of poly(ADP-ribose) polymerase disrupts organization of cytoskeletal F-actin and tissue polarity in Drosophila"J Biol Chem. 277. 6696-6702 (2002)

[文献書誌] Matsumoto K, Ito M, Hori K, Miyashita F, Suzuki S, Kishi N, Artravanis-Tsakonas S, Okano H: "Involvement of a proline-rich motif and a RING-H2 finger in a function of Deltex as a regulator of Notch signaling"Development. 129. 1049-1059 (2002)

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

[文献書誌] Shibata M, Yamawaki T, Fukuuchi Y, Okano H, Miura M: "Up-reguration 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. (in press). 141-152 (2002)

[文献書誌] Okano H, Sakakibara S, Sawamoto K, Nakamura Y, Kaneko Y, Akamatsu W, Tokunaga A, Imai T, Miyata T, Shimazaki T: "5th International Symposium on Tissue Engineering for Therapeutic Use"Elsevier science B.V.. 226 (2001)

2001 年度実績報告書

岡野栄之慶應義塾大学, 医学部, 教授 (60160694)