The role of Netrin-1 from the ventricular zone in commissural axon guidance

• Project/Area Number: 17K18332
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Nerve anatomy/Neuropathology; Neurophysiology / General neuroscience
• Research Institution: Juntendo University
• Principal Investigator: Yamauchi Kenta 順天堂大学, 医学(系)研究科(研究院), 博士研究員 (00513079)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 交連軸索 / ネトリン１ / 軸索誘導 / 脳室帯 / 腹側正中線 / 神経回路形成 / 神経発生 / 軸索ガイダンス

Outline of Final Research Achievements

Based on his observations of commissural axon (CA) growth towards the ventral midline (VM), Ramon y Cajal proposed the ‘chemotropic theory’, attraction of developing axons by a long-range diffusible cue from their targets. Netrin-1 (Ntn1) emanating from the floor plate (FP) has been assumed as the chemoattractant. However, Ntn1 is expressed in the ventricular zone (VZ), in addition to the FP, raising a possibility that Ntn1 of extra-FP origin guides CAs to the VM. In this study, we generated Ntn1 FP conditional mutant (Ntn1FP-Ko) and VZ conditional mutant mice (Ntn1VZ-Ko). If Ntn1 acts CAs as the chemoattractant, CA guidance should be disrupted in Ntn1FP-Ko mice. Contrary to this prediction, deletion of Ntn1 from the VZ highly disrupted CA guidance, whereas deletion of Ntn1 from the FP had little impact on it. Our results fail to support the chemotropic theory, rather suggest a novel mechanism that VZ-derived Ntn1 directs CAs to the VM by its local actions.

Academic Significance and Societal Importance of the Research Achievements

化学走性説に従い交連軸索が腹側正中線へと到達するというモデルはRamon y Cajalによる提唱以来、神経回路形成の基本概念となっていた。本研究の「脳室帯由来Netrin-1が短距離作動性の軸索誘導分子として機能することにより交連軸索を腹側正中線へと誘導する」という結果は神経回路形成の基本概念に再考を迫り、神経軸索再生や細胞移植といった再生医療の樹立へ向けた重要な知見となることが期待できる。

Research Products

• [Int'l Joint Research] Institute of Stem Cell Research(ドイツ)
• [Int'l Joint Research] Institute of Stem Cell Research(Germany)
• [Journal Article] Netrin-1 Derived from the Ventricular Zone, but not the Floor Plate, Directs Hindbrain Commissural Axons to the Ventral Midline (2017)
  • Author(s): Yamauchi Kenta、Yamazaki Maya、Abe Manabu、Sakimura Kenji、Lickert Heiko、Kawasaki Takahiko、Murakami Fujio、Hirata Tatsumi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 11992-11992
  • DOI: 10.1038/s41598-017-12269-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] The role of Netrin-1 from the ventricular zone in commissural axon guidance (2018)
  • Author(s): Yamauchi Kenta、Yamazaki Maya、Abe Manabu、Sakimura Kenji、Lickert Heiko、Kawasaki Takahiko、Hirata Tatsumi
  • Organizer: 第41回日本神経科学大会
• [Presentation] Netrin-1 Derived from the Ventricular Zone, but not the Floor Plate, Directs Hindbrain Commissural Axons to the Ventral Midline (2018)
  • Author(s): Yamauchi Kenta、Yamazaki Maya、Abe Manabu、Sakimura Kenji、Lickert Heiko、Kawasaki Takahiko、Murakami Fujio、Hirata Tatsumi
  • Organizer: 第123回日本解剖学会総会・全国学術集会
• [Remarks] 百年を超えて信じられてきた神経回路形成の基本原理に見直しを迫る
  • URL: https://www.nig.ac.jp/nig/ja/2017/12/research-highlights_ja/20171128.html