Analysis of the neuronal migration regulation mechanism by post-translational modification of Dab1

• Project/Area Number: 15K06746
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Keio University
• Principal Investigator: Honda Takao 慶應義塾大学, 医学部(信濃町), 講師 (30365225)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: Dab1 / Reelin / 翻訳後修飾 / reeler / yotari / dab1 / リン酸化 / 神経細胞移動 / 大脳新皮質

Outline of Final Research Achievements

Dab1 is an intracellular protein that has an essential role in neuronal migration of cerebral cortical neurons and formation of their dendrites. So far, it has been shown that posttranslational modification of tyrosine residues of Dab1 has essential roles in Reelin signaling pathway, however it remains unknown whether other amino acid residues which might be post-translationally modified are involved in Reelin-Dab1 signaling pathway. We found that some amino acids sequences are highly conserved among different species in the primary sequence of Dab1, and thus hypothesized that those sequences might be post-translationally modified. Thus, we examined the possibility of functional control of Dab1 by those amino acids. As a result, we found that the putative posttranslational modification sites are required for the correct neuronal migration.

Research Products

• [Journal Article] Proper level of cytosolic Disabled-1, which is regulated by dual nuclear translocation pathways, is important for cortical neuronal migration. (2015)
  • Author(s): Honda T and Nakajima K
  • Journal Title: Cereb. Cortex Volume: bhv162 Issue: 7 Pages: 1-18
  • DOI: 10.1093/cercor/bhv162
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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
• [Presentation] Dab1 haploinsufficiency causes invasion of superficial cortical neurons into layer I and splitting of CA1 pyramidal cell layer (2018)
  • Author(s): 本田岳夫、仲嶋一範
  • Organizer: 第123回日本解剖学会総会・全国学術集会
• [Presentation] dab1のハプロ不全は表層神経細胞の大脳皮質第一層への侵入とCA1錐体細胞層の分離を引き起こす（Haploinsufficiency of dab1 causes invasion of superficial-layer neurons into the cortical layer I and splitting of the CA1 pyramidal cell layer） (2017)
  • Author(s): 本田岳夫、仲嶋一範
  • Organizer: 2017年度生命科学系学会合同年次大会（第40回日本分子生物学会年会・第90回日本生化学会大会）
• [Presentation] Dab1 haploinsufficiency causes reduction of layer I thickness and splitting of CA1 pyramidal cell layer (2017)
  • Author(s): 本田岳夫、仲嶋一範
  • Organizer: 第60回日本神経化学会大会
• [Presentation] Dab1 haploinsufficiency causes superficial shift of later-born cortical neuron positioning and splitting of the CA1 pyramidal cell layer (Dab1のハプロ不全は大脳新皮質遅生まれニューロンの脳表層側配置と海馬CA1錐体細胞層の分離を引き起こす) (2017)
  • Author(s): 本田岳夫、仲嶋一範
  • Organizer: 第40回日本神経科学大会
• [Presentation] Reelin coupled with myelin may play a role in long term maintenance of myelin （リーリンは、ミエリンの長期維持の役割を果たしている） (2016)
  • Author(s): Kimiko Deguchi，Takao Honda, Ken-ichiro Kubo, Kazunori Nakajima,and Ken Inoue
  • Organizer: 第58回日本小児神経学会学術集会
  • Place of Presentation: 京王プラザホテル新宿、新宿（東京都）
  • Year and Date: 2016-06-03
• [Presentation] Reelin coupled with myelin may play a role in long-term maintenance of myelin (2016)
  • Author(s): Kimiko Deguchi, Takao Honda, Ken-ichiro Kubo, Kazunori Nakajima, and Ken Inoue
  • Organizer: 21st Biennial Meeting of the International Society for Developmental Neuroscience (ISDN2016)
  • Place of Presentation: Palais des Congres d’Antibes Juan les Pins, Antibes-Juan les Pins, France
  • Year and Date: 2016-05-11
• [Presentation] Analysis of the role of Dab1 nucleo-cytoplasmic transport for migration of excitatory neurons (Dab1の核細胞質間輸送が興奮性神経細胞の移動に果たす役割の解明) (2016)
  • Author(s): Takao Honda and Kazunori Nakajima
  • Organizer: 第９回神経発生討論会・難治疾患共同研究拠点共同開催学術集会
  • Place of Presentation: 東京医科歯科大学Ｍ＆Ｄタワー鈴木章夫記念講堂（東京都、文京区）
  • Year and Date: 2016-03-18
• [Presentation] C-terminal region of Reelin is required for development and maintenance of the postnatal cerebral cortex and its functions are regulated by specific proteolysis (2016)
  • Author(s): Takao Kohno, Takao Honda, Ken-ichiro Kubo, Yoshimi Nakano, Ayaka Tsuchiya, Tatsuro Murakami, Hideyuki Banno, Kazunori Nakajima, and Mitsuharu Hattori
  • Organizer: 新学術領域研究「神経細胞の多様性と大脳新皮質の構築」第3回国際シンポジウム「Neocortical Organization 3」
  • Place of Presentation: 東京大学小柴ホール（東京都、文京区）
  • Year and Date: 2016-02-11
• [Presentation] Dab1核細胞質間シャトリングの大脳新皮質層形成における役割の解明 (2015)
  • Author(s): 本田岳夫、仲嶋一範
  • Organizer: 日本解剖学会関東支部 第103回学術集会
  • Place of Presentation: 慶應義塾大学日吉キャンパス（神奈川県、横浜市）
  • Year and Date: 2015-11-07
• [Presentation] 二つの核移行経路による細胞質Dab1量の適切な調節が興奮性神経細胞移動に重要である (2015)
  • Author(s): 本田岳夫、仲嶋一範
  • Organizer: 第50回慶應ニューロサイエンス研究会
  • Place of Presentation: 慶應義塾大学信濃町キャンパス（東京都、新宿区）
  • Year and Date: 2015-10-31
• [Presentation] Importance of Reelin C-terminal region in the development and maintenance of the postnatal cerebral cortex and its regulation by specific proteolysis (2015)
  • Author(s): Takao Kohno, Takao Honda, Ken-ichiro Kubo, Yoshimi Nakano, Ayaka Tsuchiya, Tatsuro Murakami, Hideyuki Banno, Kazunori Nakajima, and Mitsuharu Hattori.
  • Organizer: Society for Neuroscience, Neuroscience 2015 meeting
  • Place of Presentation: McCormick Place, Chicago, U.S.A
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] 二つの核移行経路による細胞質Dab1量の適切な調節が大脳皮質ニューロンの移動に重要である（Proper level of cytosolic Disabled-1, which is regulated by dual nuclear translocation pathways, is important for cortical neuronal migration） (2015)
  • Author(s): 本田岳夫、仲嶋一範
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸国際会議場・神戸国際展示場（兵庫県、神戸市）
  • Year and Date: 2015-07-28
• [Presentation] 巨大分泌蛋白質リーリンのC末端領域を介した大脳皮質形成機構 (2015)
  • Author(s): 河野孝夫、本田岳夫、久保健一郎、中野良美、土屋綾香、村上達郎、阪野英幸、仲嶋一範、服部光治
  • Organizer: 第61回日本薬学会東海支部総会・大会
  • Place of Presentation: 名古屋市立大学（愛知県、名古屋市）
  • Year and Date: 2015-07-04
• [Presentation] Evidence of a link between TDP-43 and dipeptide repeat protein in c9FTD/ALS (2015)
  • Author(s): Mai Yamakawa, Daisuke Ito, Takao Honda, Ken-ichiro Kubo, Mariko Noda, and Kazunori Nakajima, and Norihiro Suzuki
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 朱鷺メッセ（新潟県、新潟市）
  • Year and Date: 2015-05-20