脳室下帯内神経幹細胞の産生とその幹細胞性維持の分子機構

• Project Area: Neural Diversity and Neocortical Organization
• Project/Area Number: 25123727
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Institute for Developmental Research, Aichi Human Service Center
• Principal Investigator: 田畑 秀典 愛知県心身障害者コロニー発達障害研究所, 神経制御学部, 室長 (80301761)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥10,790,000 (Direct Cost: ¥8,300,000、Indirect Cost: ¥2,490,000); Fiscal Year 2014: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2013: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
• Keywords: 大脳皮質 / 神経幹細胞 / 進化 / 神経分化 / 神経細胞移動 / 神経発生

Outline of Annual Research Achievements

ヒト進化過程において、脳は著しく巨大化し、ヒトの高度な精神活動を可能にしている。脳が巨大化した主要因として、脳室帯（VZ）から離脱した神経幹細胞がさらにその幹細胞性を維持しながら脳室下帯（SVZ）で自己複製を繰り返すことが挙げられる。我々は発生過程マウス大脳皮質において、SVZで分裂する集団が皮質外側部において内側部よりも多く存在することを報告した。このことから、マウスにおいてこの両者を比較することにより、SVZ分裂細胞を多く作る仕組みを解明でき、これによりヒトが進化過程で巨大脳を獲得したメカニズムに迫ることができると考えられた。マイクロアレイ、in situ hybridization、および子宮内電気穿孔法によるスクリーニングと、情報科学的な淘汰圧の解析を平行して行い、霊長類で特異的に淘汰圧が高まり、SVZ分裂細胞の産生を正に制御する分子を同定した。この分子は、マウスではSVZにまばらに発現細胞が散見されるが、霊長類（マーモセット）では強陽性細胞が密に存在する。この分子は膜結合型のリガンドとして機能し、隣接する細胞に未分化性を維持させるように働くことが予測されることから、この発現レベルの違いが、SVZの発達を決定すると考えられた。種間による発現の違いが転写調節領域の変化によるものなのかを確かめるため、ヒトおよびマウスのBACクローンから転写開始点周囲の配列を単離し、その制御下にLuciferaseを発現するベクターを構築した。これらを子宮内電気穿孔法によりマウス胎仔脳に導入し、発現強度を比較した結果、マウス脳においてもヒトの配列はマウスよりも強い転写活性を示すことが観察された。多種間ゲノム比較によりこれらをブロック分けし、責任領域を絞り込んだところ、第２イントロン上流側の極めて狭い領域がマウスとヒトの発現強度の違いに決定的な役割を果たすことが示された。

Research Progress Status

27年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

27年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Morphological characterization of Class III phosphoinositide 3-kinase during mouse brain development. (2016)
  • Author(s): Inaguma Y, Ito H, Iwamoto I, Matsumoto A, Yamagata T, Tabata H, Nagata K-I
  • Journal Title: Med Mol Morphol Volume: 49 Issue: 1 Pages: 28-33
  • DOI: 10.1007/s00795-015-0116-1
  • Peer Reviewed / Open Access
• [Journal Article] Role of the cytoplasmic isoform of RBFOX1/A2BP1 in establishing the architecture of the developing cerebral cortex. (2015)
  • Author(s): Hamada N, Ito H, Iwamoto I, Morishita R, Tabata H, Nagata K-I
  • Journal Title: Molecular Autism Volume: 6 Issue: 1 Pages: 56-56
  • DOI: 10.1186/s13229-015-0049-5
  • Peer Reviewed / Open Access
• [Journal Article] The COUP-TFII/Neuropilin-2 is a molecular switch steering diencephalon-derived GABAergic neurons in the developing mouse brain (2015)
  • Author(s): Shigeaki Kanatani, Takao Honda, Michihiko Aramaki, Kanehiro Hayashi, Ken-ichiro Kubo, Mami Ishida, Daisuke H. Tanaka, Takeshi Kawauchi, Katsutoshi Sekine, Sayaka Kusuzawa, Takahiko Kawasaki, Tatsumi Hirata, Hidenori Tabata, Per Uhlen and Kazunori Nakajima
  • Journal Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 112(36) Issue: 36
  • DOI: 10.1073/pnas.1420701112
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Analysis of cardiomyocyte movement in the developing murine heart. (2015)
  • Author(s): Hashimoto H, Yuasa S, Tabata H, Tohyama S, Seki T, Egashira T, Hayashiji N, Hattori F, Kusumoto D, Kunitomi A, Takei M, Kashimura S, Yozu G, Shimojima M, Motoda C, Muraoka N, Nakajima K, Sakaue-Sawano A, Miyawaki A, Fukuda K
  • Journal Title: Biochem Biophys Res Commun Volume: 464 Issue: 4 Pages: 1000-1007
  • DOI: 10.1016/j.bbrc.2015.07.036
  • Peer Reviewed / Open Access
• [Journal Article] Role of an adaptor protein Lin-7B in brain development: possible involvement in autism spectrum disorders. (2015)
  • Author(s): Mizuno M, Matsumoto A, Hamada N, Ito H, Miyauchi A, Jimbo EF, Momoi MY, Tabata H, Yamagata T, Nagata K.
  • Journal Title: J Neurochem Volume: 132 Issue: 1 Pages: 61-69
  • DOI: 10.1111/jnc.12943
  • Peer Reviewed / Open Access
• [Journal Article] Morphological characterization of mammalian Timeless in the mouse brain development. (2015)
  • Author(s): Inaguma Y, Ito H, Hara A, Iwamoto I, Matsumoto A, Yamagata T, Tabata H, Nagata K.
  • Journal Title: Neurosci Res Volume: 92 Pages: 21-28
  • DOI: 10.1016/j.neures.2014.10.017
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Diverse subtypes of astrocytes and their development during corticogenesis. (2015)
  • Author(s): Hidenori Tabata
  • Journal Title: Front. Neurosci. Volume: 9 Pages: 114-114
  • DOI: 10.3389/fnins.2015.00114
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] SIL1, a causative cochaperone gene of Marinesco-Sjogren syndrome, plays an essential role in establishing the architecture of the developing cerebral cortex. (2014)
  • Author(s): Hamada N, Inaguma Y, Tabata H, Iwamoto I, Mizuno M, Nishimura YV, Ito H, Morishita R, Suzuki M, Ohno K, Kumagai T, Nagata K.
  • Journal Title: EMBO Mol Med. Volume: 6 Issue: 3 Pages: 414-29
  • DOI: 10.1002/emmm.201303069
  • Peer Reviewed / Open Access
• [Journal Article] Time-lapse imaging of cell cycle dynamics during development in living cardiomyocyte. (2014)
  • Author(s): Hashimoto H, Yuasa S, Tabata H, Tohyama S, Hayashiji N, Hattori F, Muraoka N, Egashira T, Okata S, Yae K, Seki T, Nishiyama T, Nakajima K, Sakaue-Sawano A, Miyawaki A and Fukuda K.
  • Journal Title: J.Mol. Cell. Cardiol. Volume: S0022-2828(14) Pages: 97-2
  • DOI: 10.1016/j.yjmcc.2014.03.020
  • Peer Reviewed
• [Journal Article] 2.Roles of Rho small GTPases in the tangentially migrating neurons. (2014)
  • Author(s): Hidenori Ito, Rika Morishita, Hidenori Tabata, and Koh-ichi Nagata
  • Journal Title: Histol. Histopathol. Volume: 29(7) Pages: 871-879
  • Peer Reviewed
• [Journal Article] Biochemical and morphological characterization of A2BP1 in the neuronal tissue. (2013)
  • Author(s): Hamada N, Ito H, Iwamoto I, Mizuno M, Morishita R, Inaguma Y, Kawamoto S, Tabata H and Nagata K.
  • Journal Title: J Neurosci Res Volume: 91 Issue: 10 Pages: 1303-1311
  • DOI: 10.1002/jnr.23266
  • Peer Reviewed
• [Journal Article] Screening for candidate genes involved in the production of mouse subventricular zone proliferative cells and an estimation of their changes in evolutionary pressure during primate evolution (2013)
  • Author(s): Tabata H, Hachiya T, Nagata K, Sakakibara Y, Nakajima K
  • Journal Title: Front Neuroanat Volume: 7 Pages: 24-24
  • DOI: 10.3389/fnana.2013.00024
  • Peer Reviewed / Open Access
• [Presentation] グリア前駆細胞の移動様式と血管との関連 (2016)
  • Author(s): 田畑秀典、佐々木恵、稲熊裕、伊東秀記、竹林浩秀、依馬正次、池中一裕、永田浩一、仲嶋一範
  • Organizer: 第121回日本解剖学会総会・全国学術集会
  • Place of Presentation: 郡山（福島県）
  • Year and Date: 2016-03-28
  • Invited
• [Presentation] 皮質脳室帯由来グリア前駆細胞のダイナミックな移動様式（Dynamic behavior of glia progenitors derived from the cortical ventricular zone） (2015)
  • Author(s): 田畑秀典、佐々木恵、稲熊裕、伊東秀記、竹林浩秀、依馬正次、池中一裕、永田浩一、仲嶋一範
  • Organizer: 第38回日本分子生物学会年会・第88回日本生化学会大会合同大会(BMB2015)
  • Place of Presentation: 神戸（兵庫県）
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] Interaction between glia and blood vessels during cortical development (2015)
  • Author(s): Hidenori Tabata, Megumi Sasaki, Yutaka Inaguma, Hidenori Ito, Hirohide Takebayashi, Masatsugu Ema, Kazuhiro Ikenaka, Koh-ichi Nagata, and Kazunori Nakajima
  • Organizer: 第58回日本神経化学会大会
  • Place of Presentation: 大宮（埼玉県）
  • Year and Date: 2015-09-11
  • Invited
• [Presentation] Blood vessel-guided cell migration during late cortical plate development (2015)
  • Author(s): Hidenori Tabata, Megumi Sasaki, Yutaka Inaguma, Hidenori Ito, Hirohide Takebayashi, Masatsugu Ema, Kazuhiro Ikenaka, Koh-ichi Nagata, and Kazunori Nakajima
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸（兵庫県）
  • Year and Date: 2015-07-28
• [Presentation] Blood vessel-guided cell migration in the developing cerebral cortex (2015)
  • Author(s): Hidenori Tabata, Megumi Sasaki, Yutaka Inaguma, Hidenori Ito, Hirohide Takebayashi, Masatsugu Ema, Kazuhiro Ikenaka, Koh-ichi Nagata, and Kazunori Nakajima
  • Organizer: 第48回日本発生生物学会大会
  • Place of Presentation: つくば（茨城県）
  • Year and Date: 2015-06-03
• [Presentation] Functional screening of the candidate genes involving in the expansion of subventricular zone and the evolutionary analysis of them (2015)
  • Author(s): Hidenori Tabata, Tsuyoshi Hachiya, Koh-ichi Nagata, Yasubumi Sakakibara, Kazunori Nakajima
  • Organizer: Cortical Evolution Conference 2015
  • Place of Presentation: Toledo, Spain
  • Year and Date: 2015-05-18
  • Int'l Joint Research
• [Presentation] The unique migratory properties of glial progenitors derived from the cortical ventricular zone（皮質脳室帯由来グリア前駆細胞がとる特徴的な移動様式） (2014)
  • Author(s): Hidenori Tabata, Megumi Sasaki, Hirohide Takebayashi, Masatsugu Ema, Kazuhiro Ikenaka, Koh-ichi Nagata, Kazunori Nakajima
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: 横浜（神奈川県）
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] The migration of glial progenitors derived from the cortical ventricular zone (2014)
  • Author(s): Hidenori Tabata, Megumi Sasaki, Hirohide Takebayashi, Masatsugu Ema, Kazuhiro Ikenaka, Koh-ichi Nagata, Kazunori Nakajima
  • Organizer: Cortical Development Conference 2014
  • Place of Presentation: Crete, Greece
  • Year and Date: 2014-05-22 – 2014-05-25
• [Presentation] Functional screening of the genes involved in the production of progenitor cells in the subventricular zone in mice (2013)
  • Author(s): Hidenori Tabata, Yasubumi Sakakibara, Koh-ichi Nagata, and Kazunori Nakajima
  • Organizer: Society for Neuroscience, Neuroscience 2013 Meeting
  • Place of Presentation: San Diego, California
  • Year and Date: 2013-11-09 – 2013-11-13
• [Presentation] 脳室下帯分裂細胞の産生調節に関わる分子の探索（Screening of the genes involving in the production of progenitor cells in the subventricular zone） (2013)
  • Author(s): 田畑秀典、榊原康文、永田浩一、仲嶋一範
  • Organizer: 第36回日本神経科学大会・第56回日本神経化学会大会・第23回日本神経回路学会大会合同大会（Neuro2013）
  • Place of Presentation: 京都
  • Year and Date: 2013-06-20 – 2013-06-23
• [Presentation] Histological organization of mouse and primate subventricular zone in the developing cerebral neocortex (2013)
  • Author(s): Hidenori Tabata, Satoshi Yoshinaga, Yasubumi Sakakibara, Koh-ichi Nagata, Kazunori Nakajima
  • Organizer: Neuro2013 Satellite Symposium “Molecular & Cellular Mechanisms of Brain Development & Evolution”
  • Place of Presentation: Kyoto
  • Year and Date: 2013-06-19