A molecular study of methyl-CpG binding protein 2 (MeCP2) dysfunction leaded to Rett syndrome phenotype

• Project/Area Number: 18390304
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: ITO Masayuki National Center of Neurology and Psychiatry, 神経研究所疾病研究第二部, 室長 (50243407)
• Co-Investigator(Kenkyū-buntansha): KURIMASA Akihiro 鳥取大学, 大学院・医学研究科, 准教授 (80343276) ; 井手 秀平 国立精神・神経センター, 研究生 (80425701)
• Co-Investigator(Renkei-kenkyūsha): IDE Shuuhei 国立精神・神経センター, 神経研究所疾病研究第2部, 研究生 (80425701)
• Project Period (FY): 2005 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥14,120,000 (Direct Cost: ¥11,900,000、Indirect Cost: ¥2,220,000); Fiscal Year 2008: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2007: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2006: ¥4,500,000 (Direct Cost: ¥4,500,000)
• Keywords: メチル化結合タンパク2 / レット症候群 / エピジェネティック / MeCP2 / モデルマウス

Research Abstract

レット症候群(RTT)は主に女児にみられる自閉性発達障害で、病態としてモノアミン系神経細胞の障害などがある。RTTの原因遺伝子は、DNAメチル化による転写抑制機構の中核であるMeCP2であり、この遺伝子発現抑制機構の破綻が病態形成の第一段と考えられている。RTTの症状の多様性や遺伝様式の複雑な部分を説明するのに、X染色体上にあるMeCP2のインプリンティングとX染色体不活化の関与を明らかにした。
我々が開発した遺伝子改変マウスと人工染色体を組み込んだA9細胞を用いて、X染色体のエピジェネティック制御機構の関与する疾患の病態解明とMeCP2 isoformの研究を行った。その結果、親アレルの違いによる胎仔発生率の違いを明らかにした。

Research Products

• [Journal Article] Phosphatidyl ethanolamine with increased polyunsaturated fatty acids in compensation for plasmalogen defect in the Zellweger syndrome brain. (2009)
  • Author(s): Saitoh M, Itoh M, Takashima S, Mizuguchi M, Iwamori M.
  • Journal Title: Neurosci Lett 449 Pages: 164-167
  • Peer Reviewed
• [Journal Article] Aluminum accumulation in myelin sheath of progressive leukoencephalopathy. (2008)
  • Author(s): Itoh M, Suzuki Y, Ohsawa, M, Ozuka N, Sugai K, Otsuki T, Goto Y.
  • Journal Title: J Child Neurol 23 Pages: 938-943
  • Peer Reviewed
• [Journal Article] Brainstem monoamine pathology of neonatal hypoxi c-ischemic brain damage : a model of acute stage of neonatal asphyxia (2008)
  • Author(s): Shiraishi M, Takizawa Y, Ide S, Obonai T, Goto Y, Itoh M
  • Journal Title: Brain Res 1213 Pages: 120-126
  • Peer Reviewed
• [Journal Article] Aluminum accumulation in myelin sheath of progressive leukoen cephalopathy (2008)
  • Author(s): Itoh M, Suzuki Y, Ohsawa, M, Ozuka N, Sugai K, Otsuki T, Goto Y.
  • Journal Title: J Child Neurol 23 Pages: 938-943
  • Peer Reviewed
• [Journal Article] Increase of ceramide monohexoside and dipalmitoyl glycerophospholipids in the brain of Zellweger syndrome. (2007)
  • Author(s): Saitoh M, Sakakihara Y, Mizuguchi M, Itoh M, Takashima S, Iwamori M, Kamoshita S, Igarashi T.
  • Journal Title: Neurosci Lett 417 Pages: 165-170
  • Peer Reviewed
• [Journal Article] Methyl CpG-binding protein 2 (a mutation of which causes Rett syndrome) directly regulates insulin-like growth factor binding protein 3 in mouse and human brains. (2007)
  • Author(s): Itoh M, Ide S, Takashima S, Kudo S, Nomura Y, Segawa M, Kubota T, Mori H, Tanaka S, Horie H, Tanabe Y, Goto Y
  • Journal Title: J Neuropathol Exp Neurol 66 Pages: 117-123
  • Peer Reviewed
• [Journal Article] 疾患解明Overview Rett 症候群 エピジェネティクスの理解を進展させた精神発達障害疾患 (2007)
  • Author(s): 久保田健夫、伊藤雅之
  • Journal Title: 実験医学 25 Pages: 423-428
• [Journal Article] Ku70/80 modulates ATM and ATR signaling pathways in response to DNA double strand breaks. (2007)
  • Author(s): Tomimatsu N, Tahimic CG, Otsuki A, Burma S, Fukuhara A, Sato K, Shiota G, Oshimura M, Chen DJ, Kurimasa A.
  • Journal Title: J Biol Chem 282 Pages: 10138-10145
  • NAID: 130007000861
• [Journal Article] Methyl CpG-Bindillg Protein 2,Whose Mutation Causes Rett Sy.ndrome,Directly Regulates Insulin-like Growth Factor Binding ProteSn 3 in Mouse and Hulnan Brains (2007)
  • Author(s): Itoh M, Ide S, Takashima S, Kudo S, Nomura Y, Segawa M, Kubota T, Mori H, Tanaka S, Horie H, Tanabe Y, Geto Y.
  • Journal Title: J Neuropathol Exp Neurol 66 Pages: 117-123
  • Peer Reviewed
• [Journal Article] Chemical Chaperone Therapy: Clinical Effect in Murine G_<M1>-Ganghosidosis (2007)
  • Author(s): Suzuki Y, lchinomiya S, Kurosawa M, Ohkubo M, Watanabe H, Iwasaki H, Matsuda J, Noguchi Y, Takimoto K, Itoh M, Tabe M, Iida M, Kubo T, Ogawa S, Nanba E, Higaki K, Ohno K, Brady RO.
  • Journal Title: Ann Neurol 62 Pages: 671-675
  • Peer Reviewed
• [Journal Article] Methyl CpG-Binding Protein 2, Whose Mutation Causes Rett Syndrome, Directly Regulates Insulin-like Growth Factor Binding Protein 3 in Mouse and Human Brains (2007)
  • Author(s): Itoh M, Ide S, Takashima S, Kudo S, Nomura Y, Segawa M, et al.
  • Journal Title: J Neuropathol Exp Neurol 66 Pages: 117-123
• [Journal Article] Secretin receptor deficient mice exhibit impaired synaptic plasticity and social behavior. (2006)
  • Author(s): Nishijima I, Yamagata T, Spencer CM, Weeber EJ, Alekseyenko O, Sweatt JD, Momoi M, Ito M, Armstrong D, Nelson D, Paylor R, Bradley A.
  • Journal Title: Hum Mol Genet 15 Pages: 3241-3250
  • Peer Reviewed
• [Journal Article] Human artificial chromosomevectors meet stem cells: new prospects for gene delivery. (2006)
  • Author(s): Ren X, Tahimic CG, Katoh M, Kurimasa A, Inoue T, Oshimura M.
  • Journal Title: Stem Cell Rev 2 Pages: 43-50
• [Presentation] MONOAMINE ALTERATION IN BRAINSTEM OF NEONATAL HYPOXIC-ISCHEMIC BRAIN DAMAGE (2008)
  • Author(s): Itoh M
  • Organizer: The 2nd Congress of the European Academy of Paediatrics
  • Place of Presentation: Nice, France
  • Year and Date: 2008-10-27
• [Presentation] MECP2 DIRECTLY REGULATES INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN 3 EXPRESSION (2008)
  • Author(s): Itoh M
  • Organizer: The 9th Annual Rett Syndrome Symposium
  • Place of Presentation: Paris, France
  • Year and Date: 2008-10-12
• [Presentation] Delayed Synaptic Maturation of Rett Syndrome model mice brain. (2008)
  • Author(s): Itoh M.
  • Organizer: The 9th Annual Rett Syndrome Symposium.
  • Place of Presentation: Chicago, IL
  • Year and Date: 2008-06-24
• [Presentation] MeCP2 directly regulates insulin-like growth factor binding protein 3 expression. (2008)
  • Author(s): Itoh M.
  • Organizer: The 6th World Rett Syndrome Congress - A Hand Link from Gene to Care.
  • Place of Presentation: Paris, October
• [Presentation] MeCP2 directly regulates insulin-like growth factor binding protein 3 expression in brains. (2007)
  • Author(s): Itoh M.
  • Organizer: The 8th Annual Rett Syndrome Symposium.
  • Place of Presentation: Chicago, IL
  • Year and Date: 2007-06-26
• [Presentation] MeCP2 directly regulates insulin-like growth factor binding protein 3 expression in brains (2007)
  • Author(s): M.Itoh
  • Organizer: The 8th Annual Rett Syndrome Symposium
  • Place of Presentation: シカゴ、アメリカ合衆国
  • Year and Date: 2007-06-26
• [Presentation] Pathogenesis of Rett syndrome, advance study of MeCP2 molecular mechanism. (2006)
  • Author(s): Itoh M.
  • Organizer: Symposium IV, Brain Development Disorders, The 4th Congress of Federation of Asian-Oceanian Neuroscience Societies
  • Place of Presentation: Hong Kong
  • Year and Date: 2006-11-30
• [Presentation] A histopathological study of premature and mature infants with pontosubicular neuron necrosis. (2006)
  • Author(s): Itoh M, Takashima S.
  • Organizer: Developmental/Pediatric Workshop. The 16th. International congress of Neuropathology
  • Place of Presentation: San Francisco
  • Year and Date: 2006-09-12
• [Presentation] エピジェネティクスが関与する自閉症疾患レット症候群の発症機転(Pathogenesis of Rett syndrome, an epigenetic autistic disease). (2006)
  • Author(s): Itoh M.
  • Organizer: エピジェネティク神経科学シンポジウム, 第29回日本神経科学会議
  • Place of Presentation: 京都
  • Year and Date: 2006-07-12
• [Presentation] MeCP2 directly regulates insulin-like growth factor binding protein 3 expression in brains. (2006)
  • Author(s): Itoh M, Ide S, Takashima S, Kudo S, Nomura Y, Segawa M, Kubota T, Mori H, Tanaka S, Horie H, Tanabe, Goto Y.
  • Organizer: The tenth International Child Neurology Congress.
  • Place of Presentation: Montreal, Canada
• [Book] 小児大脳変性疾患の病理.小児神経学. (2008)
  • Author(s): 伊藤雅之
  • Publisher: 診断と治療社
• [Book] 大脳の発達過程と障害. ことばとこころの発達と障害. (2007)
  • Author(s): 伊藤雅之
  • Publisher: 永井書店