Clarification of control mechanism in lung and bronchial by Wnt signaling

• Project/Area Number: 25861669
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatric surgery
• Research Institution: Research Institute, Osaka Medical Center for Maternal and Child Health (2015); Osaka University (2013-2014)
• Principal Investigator: IBUKA SOUJI 地方独立行政法人大阪府立病院機構大阪府立母子保健総合医療センター(研究所), その他部局等, 小児外科・診療主任 (50625027)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: P2Y2R / 上皮管腔形成 / インテグリン / フィブロネクチン / Wnt / EGF / tubulogenesis / integrins / fibronectin / 管腔形成 / 上皮細胞 / Wnt関連因子 / 増殖因子

Outline of Final Research Achievements

We used rat intestinal epithelial IEC6 cells to investigate tubulogenesis and we found that tubular formation was induced by a combination of Wnt3a and EGF signaling during 3D culture. Wnt3a and EGF induced the expression of the P2Y2 receptor, and knockdown of P2Y2R suppressed tubular formation. The Arg-Gly-Asp (RGD) sequence of P2Y2R has been shown to interact with integrins, and a P2Y2R mutant lacking integrin-binding activity was unable to induce tubular formation. P2Y2R expression inhibited the interaction between integrins and fibronectin. Inhibition of integrin and fibronectin binding by treatment with the cyclic RGD peptide and fibronectin knockdown induced tubular formation in the presence of EGF alone, but a fibronectin coat suppressed Wnt3a- and EGF-induced tubular formation. These results suggest that Wnt3a- and EGF-induced P2Y2R expression causes tubular formation by preventing the binding of integrins and fibronectin rather than by mediating nucleotide responses.

Research Products

• [Journal Article] The P2Y2 receptor promotes Wnt3a and EGF-induced epithelial tubular formation of IEC6 cells by binding to integrins. (2015)
  • Author(s): Ibuka, S., Matsumoto, S., Fujii, S., Kikuchi, A.
  • Journal Title: J Cell Sci. Volume: 128(11) Issue: 11 Pages: 2156-2168
  • DOI: 10.1242/jcs.169060
  • Peer Reviewed
• [Journal Article] A combination of Wnt and growth factor signaling induces Arl4c expression to form epithelial tubular structures. (2014)
  • Author(s): Matsumoto, S., Fujii, S., Sato, A., Ibuka, S., Kagawa, Y., Ishii, M., and Kikuchi, A.
  • Journal Title: EMBO J Volume: 33 Issue: 7 Pages: 702-718
  • DOI: 10.1002/embj.201386942
  • Peer Reviewed
• [Presentation] The P2Y2 receptor promotes Wnt3a and EGF-induced tubular formation of IEC6 cells by inhibition of integrin-mediated cell adhesion (2015)
  • Author(s): Souji Ibuka, Shinji Matsumoto, Shinsuke Fujii, Akira Kikuchi, Hiroomi Okuyama
  • Organizer: EUPSA 2015, 16th European Paediatric Surgeons Association's Annual Congress
  • Place of Presentation: Slovenia, Ljubljana
  • Year and Date: 2015-06-17
  • Int'l Joint Research
• [Presentation] Wnt3aとEGFシグナルによって発現するP2Y2Rは上皮管腔形成を促進する (2015)
  • Author(s): 井深 奏司，松本 真司，藤井 慎介, 菊池 章, 奥山 宏臣
  • Organizer: 第52回日本小児外科学会学術集会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2015-05-28
• [Presentation] Wnt/EGFシグナルにより発現するP2ry2は上皮管腔形態形成を制御する (2014)
  • Author(s): 井深 奏司, 松本 真司, 菊池 章
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2014-10-16
• [Presentation] Wnt/EGFシグナルによるP2ry2の発現は上皮管腔形態形成を制御する
  • Author(s): 井深 奏司，松本 真司，菊池 章
  • Organizer: 第36回 日本分子生物学会年会
  • Place of Presentation: 神戸国際会議場
• [Remarks] P2Y2受容体の発現を介する上皮管腔組織形成
  • URL: http://www.med.osaka-u.ac.jp/pub/molbiobc/research04.html