Elucidating the role of Ras downstream pathways and Ras signal strength in angio/lymphangiogenesis and epidermal morphogenesis

• Project/Area Number: 25460263
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General anatomy (including histology/embryology)
• Research Institution: The University of Tokyo
• Principal Investigator: ICHISE Hirotake 東京大学, 医科学研究所, 講師 (10313090)
• Co-Investigator(Kenkyū-buntansha): ICHISE Taeko 東京大学, 医科学研究所, 助教 (00396863)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: マウス / Ras / Erk / リンパ管 / 内皮間葉移行 / 表皮 / Raf / PI3キナーゼ / RalGEF / 皮膚表皮 / トランスジェニックマウス / MAPキナーゼ / リンパ管内皮細胞

Outline of Final Research Achievements

Recent studies have demonstrated that endothelial-to-mesenchymal transition (EndMT) is implicated in human diseases. However, the molecular basis of EndMT remains largely unknown. We found that α-smooth muscle actin-positive lymphatic endothelial cells (LECs) appear in mouse lymphedematous skin in vivo. Mouse immortalized LECs lost their characteristics and underwent EndMT when cultured in FGF2-depleted medium in vitro. FGF2 depletion acted synergistically with TGFβ to induce EndMT. In contrast, H-Ras-overexpressing LECs were resistant to EndMT. Activation of Ras not only upregulated FGF2-induced activation of the Erk MAP kinases and LEC-specific gene expression, but also suppressed TGFβ-induced activation of Smad2 by modulating Smad2 phosphorylation by Erk MAPKs. Our findings provide a new insight into the FGF2-Ras-MAPK-dependent mechanism that maintains and modulates the LEC trait.

Research Products

• [Journal Article] Phospholipase Cγ2 Is Required for Luminal Expansion of the Epididymal Duct during Postnatal Development in Mice. (2016)
  • Author(s): Ichise H, Ichise T, Yoshida N.
  • Journal Title: PLoS One Volume: 11 Issue: 3 Pages: e0150521-e0150521
  • DOI: 10.1371/journal.pone.0150521
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of a tamoxifen-inducible Cre-driver mouse strain for widespread and temporal genetic modification in adult mice (2016)
  • Author(s): Hirotake Ichise, Akiko Hori, Seiji Shiozawa, Saki Kondo, Yumi Kanegae, Izumu Saito, Taeko Ichise, and Nobuaki Yoshida
  • Journal Title: Experimental Animals Volume: 65 Issue: 3 Pages: 231-244
  • DOI: 10.1538/expanim.15-0126
  • NAID: 130006882370
  • ISSN: 0007-5124, 1341-1357, 1881-7122
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Cd6 gene as a permissive locus for targeted transgenesis in the mouse. (2014)
  • Author(s): Ichise, H., Ichise, T., Sasanuma, H., Yoshida, N.
  • Journal Title: genesis Volume: 52 Issue: 5 Pages: 440-450
  • DOI: 10.1002/dvg.22779
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] FGF2-induced Ras-MAPK signalling maintains lymphatic endothelial cell identity by upregulating endothelial-cell-specific gene expression and suppressing TGFβ signalling through Smad2. (2014)
  • Author(s): Ichise, T., Yoshida, N., Ichise, H.
  • Journal Title: Journal of Cell Science Volume: 127 Pages: 845-857
  • DOI: 10.1242/jcs.137836
  • Peer Reviewed