Left-right symmetry breaking in vertebrates: cilia-dependent and independent mechanisms

• Project/Area Number: 20H00472
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 44:Biology at cellular to organismal levels, and related fields
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Hamada Hiroshi 国立研究開発法人理化学研究所, 生命機能科学研究センター, チームリーダー (00208589)
• Co-Investigator(Kenkyū-buntansha): 清成 寛 国立研究開発法人理化学研究所, 生命機能科学研究センター, チームリーダー (40721048) ; 内川 昌則 大阪大学, 大学院生命機能研究科, 助教 (80346147)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥43,680,000 (Direct Cost: ¥33,600,000、Indirect Cost: ¥10,080,000); Fiscal Year 2022: ¥12,220,000 (Direct Cost: ¥9,400,000、Indirect Cost: ¥2,820,000); Fiscal Year 2021: ¥14,040,000 (Direct Cost: ¥10,800,000、Indirect Cost: ¥3,240,000); Fiscal Year 2020: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
• Keywords: 左右非対称性 / 繊毛 / Nodal / 生物多様性 / メカノセンサー / 遺伝子発現制御

Outline of Research at the Start

私たちの体は、頭尾・背腹・左右という３つの極性（体軸）を持っている。なかでも左右非対称な形態は、発生のどの時期において、どのような仕組みで生じるのか？　本研究では，２つの異なる脊椎動物において、左右非対称性の起源を明らかにしたい。すなわち、マウスにおいては、繊毛に依存して方向性を持った水流が生じ、その水流を感知する機構を解明する。一方、繊毛に依存しない爬虫類や鳥類においては、繊毛がなくても対称性が破られる機構を調べることで非対称性の起源に迫る。これら２種類の脊椎動物における機構を比較することで、対称性が破られるメカニズムの多様性を明らかにしたい。

Outline of Final Research Achievements

We aimed to understand the mechanism that brings left-right (L-R) asymmetry of body, by using two different vertebrates. In the mouse that depends on the cilia-generated fluid flow at the node, the flow is sensed by immotile cilia as mechanical force via a mechanosensor ion channel. As the result, Ca2+ enters node cells on the left side, and degrades the target mRNA via an RNA-binding protein Bicc1. Immotile cilia can sense the direction of the fluid flow because the ion channel protein is preferentially localized to the dorsal side of immotile cilia on left and right sides. In reptiles and birds, which do not depend on cilia or flow at the node, Nodal expression is L-R asymmetric at the node. We have searched for a transcriptional enhancer of Nodal gene, and have identified an enhancer responsible for L-R asymmetric expression at the node.

Academic Significance and Societal Importance of the Research Achievements

左右非対称性を決める水流が感知される機構が解明された点は、学術的に大きな意義を持つ。とくに、『水流は左右を決める分子を運搬するのか、それとも力学刺激として感知されるのか？』という長年の疑問に答えを出せたことは大きな進展であった。一方で、繊毛や水流に依存せずに対称性を破る鳥類や爬虫類では、その機構は不明であったが、Nodalの非対称な発現を規定するエンハンサーを同定できたことで、重要な糸口を得ることができた。

Research Products

• [Int'l Joint Research] University of Hohenheim(ドイツ)
• [Int'l Joint Research] EPFL(スイス)
• [Int'l Joint Research] EPFL(スイス)
• [Int'l Joint Research] National University of Singapore(シンガポール)
• [Journal Article] Immotile cilia mechanically sense the direction of fluid flow for left-right determination (2023)
  • Author(s): Katoh Takanobu A.、Omori Toshihiro、Mizuno Katsutoshi、Sai Xiaorei、Minegishi Katsura、Ikawa Yayoi、Nishimura Hiromi、Itabashi Takeshi、Kajikawa Eriko、Hiver Sylvain、Iwane Atsuko H.、Ishikawa Takuji、Okada Yasushi、Nishizaka Takayuki、Hamada Hiroshi
  • Journal Title: Science Volume: 379 Issue: 6627 Pages: 66-71
  • DOI: 10.1126/science.abq8148
  • Peer Reviewed / Open Access
• [Journal Article] Left-Right Asymmetric Expression of the Nodal-Lefty-Pitx2 Module in Developing Turtle Forebrain. (2022)
  • Author(s): Kajikawa, E., Miki, T., Takeda, M., Kiyonari, H. and Hamada, H.
  • Journal Title: Front. Cell Dev. Biol. Volume: 10 Pages: 929808-929808
  • DOI: 10.3389/fcell.2022.929808
  • Peer Reviewed
• [Journal Article] Planar cell polarity?dependent asymmetric organization of microtubules for polarized positioning of the basal body in node cells (2022)
  • Author(s): Sai Xiaorei、Ikawa Yayoi、Nishimura Hiromi、Mizuno Katsutoshi、Kajikawa Eriko、Katoh Takanobu A.、Kimura Toshiya、Shiratori Hidetaka、Takaoka Katsuyoshi、Hamada Hiroshi、Minegishi Katsura
  • Journal Title: Development Volume: - Issue: 9 Pages: 200315-200315
  • DOI: 10.1242/dev.200315
  • Peer Reviewed
• [Journal Article] Fluid flow-induced left-right asymmetric decay of Dand5 mRNA in the mouse embryo requires a Bicc1-Ccr4 RNA degradation complex (2021)
  • Author(s): Minegishi Katsura、Rothe Benjamin、Komatsu Kaoru R.、Ono Hiroki、Ikawa Yayoi、Nishimura Hiromi、Katoh Takanobu A.、Kajikawa Eriko、Sai Xiaorei、Miyashita Emi、Takaoka Katsuyoshi、Bando Kana、Kiyonari Hiroshi、Yamamoto Tadashi、Saito Hirohide、Constam Daniel B.、Hamada Hiroshi
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 4071-4071
  • DOI: 10.1038/s41467-021-24295-2
  • NAID: 120007141958
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Bicc1 and Dicer regulate left-right patterning through post-transcriptional control of the Nodal-inhibitor Dand5. (2021)
  • Author(s): . Maerker, M., Getwan, M., Dowdle, M.E., McSheene, J.C., Gonzalez, V., Pelliccia, J.L., Hamilton, D.S., Yartseva, V., Tingler M., Minegishi, K., Vick, P., Giraldez, A.J., Hamada, H., Burdine, R.D., Sheets, M.D., Blum, M, and Schweickert, A.
  • Journal Title: Nat. Commun. Volume: 12 Issue: 1 Pages: 5482-5482
  • DOI: 10.1038/s41467-021-25464-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The many faces of Sox2 function in neural crest development (2021)
  • Author(s): Wakamatsu Yoshio、Uchikawa Masanori
  • Journal Title: Development, Growth & Differentiation Volume: 63 Issue: 1 Pages: 93-99
  • DOI: 10.1111/dgd.12705
  • Peer Reviewed / Open Access
• [Journal Article] Sox2 gene regulation via the D1 enhancer in embryonic neural tube and neural crest by the combined action of SOX2 and ZIC2 (2020)
  • Author(s): Iida Hideaki、Furukawa Yoko、Teramoto Machiko、Suzuki Hitomi、Takemoto Tatsuya、Uchikawa Masanori、Kondoh Hisato
  • Journal Title: Genes to Cells Volume: In press Issue: 4 Pages: 242-256
  • DOI: 10.1111/gtc.12753
  • Peer Reviewed / Open Access
• [Journal Article] Role of Ca2+ transients at the node of the mouse embryo in breaking of left-right symmetry (2020)
  • Author(s): Mizuno Katsutoshi、Shiozawa Kei、Katoh Takanobu A.、Minegishi Katsura、Ide Takahiro、Ikawa Yayoi、Nishimura Hiromi、Takaoka Katsuyoshi、Itabashi Takeshi、Iwane Atsuko H.、Nakai Junichi、Shiratori Hidetaka、Hamada Hiroshi
  • Journal Title: Science Advances Volume: 6 Issue: 30
  • DOI: 10.1126/sciadv.aba1195
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CFAP53 regulates mammalian cilia-type motility patterns through differential localization and recruitment of axonemal dynein components. (2020)
  • Author(s): Ide T, Twan WK, Lu H, Ikawa Y, Lim LX, Henninger N, Nishimura H, Takaoka K, Narasimhan V, Yan X, Shiratori H, Roy S, Hamada H.
  • Journal Title: PLoS Genet. Volume: 16(12) Issue: 12 Pages: e1009232-e1009232
  • DOI: 10.1371/journal.pgen.1009232
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Remarks] 体づくりの左右非対称性を決める「力」の発見
  • URL: https://www.riken.jp/press/2023/20230112_2/index.html
• [Remarks] 体の左右非対称性はmRNAの分解から始まる
  • URL: https://www.riken.jp/press/2021/20210730_3/index.html