Origin of anterior-posterior axis in the mouse embryos

• Project/Area Number: 19K23756
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0702:Biology at cellular to organismal levels, and related fields
• Research Institution: The University of Tokushima
• Principal Investigator: TAKAOKA Katsuyoshi 徳島大学, 先端酵素学研究所, 准教授 (90551044)
• Project Period (FY): 2019-08-30 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: マウス胚 / 前後軸 / 体軸 / 着床 / 非対称性 / 不妊治療 / 子宮 / 老化 / 初期流産 / 加齢

Outline of Research at the Start

これまで「丸い哺乳類の受精卵がいつどのようにして非対称な形態を獲得するのだろうか？」という発生学の命題に対し、マウス胚の3つの体軸の中で最も早期に形成される前後軸の初期決定機構をさかのぼって解析することでアプローチしてきた。さらに、前後軸方向を決定する細胞群DVEの位置は受精後3.5日胚のNodal発現開始細胞によって決定され、少なくとも受精後3.5日胚は前後方向の基盤となる非対称な分子情報を獲得していることを明らかにした。本研究では、さらに遡って「Nodalが一部の細胞のみで発現するメカニズムを明らかにする」ことで、マウス胚の前後軸の起源の解明に迫る

Outline of Final Research Achievements

One fundamental question in developmental biology is how an initially round fertilized egg becomes an elaborately shaped embryo. In Drosophila, whose eggs are elliptical in shape, the anterior-posterior (A-P) axis is specified by asymmetrical distribution of maternal determinants. In mammals such as humans and mice. The A-P axis, the first axis established in mammals, is determined by distal visceral endoderm (DVE). How prospective DVE cells are selected in the embryo, however, has remained unclear. We showed that, in mouse embryos, the DVE is formed through a negative feedback by Lefty1 and Nodal.The DVE then drives the establishment of the A-P axis by migrating to the future anterior side. We made an hypothesis; The DVE cells that determines the anterior-posterior axis direction is produced by the Nodal signals of the ovary, uterus, and embryo acting as a spatiotemporal network, and maternal aging disrupts the patterning of the head-determining cell group AVE.

Academic Significance and Societal Importance of the Research Achievements

本研究は、前後軸の起源を明らかにするという、発生学の本質にアプローチする壮大な研究である。ショウジョウバエを含む多くの生物はすでに卵子の段階で分子レベルの非対称情報を獲得しており、それら分子レベルの非対称情報が後の体軸情報を提供する。それに対して、ヒトやマウスといった胎生動物がいつどのようにして体軸の基となる非対称な分子情報を獲得するのかは長らく不明であり、発生学の命題であった。本研究が完了した場合、発生学の命題が明らかになり、マウス胚発生学の歴史の中で重要なマイルストーンとなる。

Research Products

• [Int'l Joint Research] National University of Singapore(シンガポール)
• [Int'l Joint Research] University Hospital Munster(ドイツ)
• [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
• [Journal Article] CFAP45 deficiency causes situs abnormalities and asthenospermia by disrupting an axonemal adenine nucleotide homeostasis module (2020)
  • Author(s): Gerard W. Dougherty, Katsutoshi Mizuno, 他25名, Ide T, Twan WK, 他9名, Aviram M, Kaiser T, Memari Y, Dzeja PP, Dworniczak B, Ueffing M, Roepman R, Bartscherer K, Katsanis N, Davis EE, Amirav I, Hamada H, Omran H.
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 5520-5520
  • DOI: 10.1038/s41467-020-19113-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Rab7-Mediated Endocytosis Establishes Patterning of Wnt Activity through Inactivation of Dkk Antagonism (2020)
  • Author(s): Kawamura Nobuyuki、Takaoka Katsuyoshi、Hamada Hiroshi、Hadjantonakis Anna-Katerina、Sun-Wada Ge-Hong、Wada Yoh
  • Journal Title: Cell Reports Volume: 31 Issue: 10 Pages: 107733-107733
  • DOI: 10.1016/j.celrep.2020.107733
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ciliogenesis‐coupled accumulation of IFT‐B proteins in a novel cytoplasmic compartment (2019)
  • Author(s): Lamri Lynda、Twan Wang Kyaw、Katoh Takanobu A.、Botilde Yanick、Takaoka Katsuyoshi、Ikawa Yayoi、Nishimura Hiromi、Fukumoto Akemi、Minegishi Katsura、Mizuno Katsutoshi、Hamada Hiroshi
  • Journal Title: Genes to Cells Volume: 24 Issue: 11 Pages: 731-745
  • DOI: 10.1111/gtc.12722
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Uncovering the mystery of mammalian oocyte-embryo development. (2019)
  • Author(s): Takaoka K
  • Organizer: 第42回日本分子生物学会年会
• [Book] Bio Clinica (2021)
  • Author(s): 高岡勝吉
  • Total Pages: 2
  • Publisher: 北隆館
• [Book] Precision Medicine (2019)
  • Author(s): 高岡勝吉
  • Total Pages: 85
  • Publisher: 北隆館／ニューサイエンス社