Regulation of exocrine glands development by Wnt signaling

• Project/Area Number: 15K08272
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Osaka University
• Principal Investigator: Matsumoto Shinji 大阪大学, 医学系研究科, 助教 (20572324)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 外分泌腺 / 唾液腺 / Wnt / 腺房 / 導管 / 分化 / KIT / Wntシグナル / 腺房分化 / 導管形成

Outline of Final Research Achievements

Growth factor signaling is involved in the development of various tubular organs, but how signaling regulates organ early morphogenesis and late differentiation remains to be clarified. Experiments using genetically manipulated mice and organ cultures revealed that Wnt signaling at early stage of submandibular salivary gland (SMG) development inhibits end bud differentiation into proacini by suppressing KIT expression through the upregulation of the transcription factor Myb. In addition, Wnt signaling at the SMG development early stage promoted the expansion of end bud progenitor, leading to duct structure formation. In contrast, Wnt signaling reduction at a late stage of SMG development promoted end bud differentiation into proacini and suppressed duct morphogenesis. These results suggest that Wnt signaling activity fine-tunes the timing of end bud morphogenesis and differentiation into proacini, in co-operation with KIT signaling during salivary gland organogenesis.

Academic Significance and Societal Importance of the Research Achievements

本研究では、胎生期唾液腺をモデルとして、今回新たに確立した各種上皮単独培養法を用いて、生体内で起きている複雑な形態形成と分化のプロセスをin vitroで再現した。
本研究成果は種々の管腔臓器の発生と再生の仕組みを理解するための分子基盤を提供するものであり、再生医療を現実のものにするための必須の事項である。また、正常な組織形成・維持のメカニズムの解明はその破綻に基づくがんの病態を理解する上でも重要であり、本研究は学術的に重要であるばかりでなく、医療という側面において社会的意義も大きい。

Research Products

• [Journal Article] Wnt/β-catenin signaling, which is activated in odontomas, reduces Sema3A expression to regulate odontogenic epithelial cell proliferation and tooth germ development. (2019)
  • Author(s): Fujii Shinsuke、Nagata Kengo、Matsumoto Shinji、Kohashi Ken-ichi、Kikuchi Akira、Oda Yoshinao、Kiyoshima Tamotsu、Wada Naohisa
  • Journal Title: SCIENTIFIC REPORTS Volume: 9 Pages: 4257-4257
  • DOI: 10.1038/s41598-019-39686-1
  • Peer Reviewed / Open Access
• [Journal Article] Chemically Modified Antisense Oligonucleotide Against ARL4C Inhibits Primary and Metastatic Liver Tumor Growth. (2019)
  • Author(s): Harada Takeshi、Matsumoto Shinji、Hirota Suguru、Kimura Hirokazu、Fujii Shinsuke、Kasahara Yuuya、Gon Hidetoshi、Yoshida Toshihiko、Itoh Tomoo、Haraguchi Naotsugu、Mizushima Tsunekazu、Noda Takehiro、Eguchi Hidetoshi、Nojima Satoshi、Morii Eiichi、Fukumoto Takumi、Obika Satoshi、Kikuchi Akira
  • Journal Title: Mol. Cancer Ther. Volume: 18 Pages: 602-612
  • DOI: 10.1158/1535-7163.mct-18-0824
  • Peer Reviewed
• [Journal Article] Arl4c is a key regulator of tubulogenesis and tumourigenesis as a target gene of Wnt-β-catenin and growth factor-Ras signalling. (2017)
  • Author(s): Matsumoto, S., Fujii, S., Kikuchi, A.
  • Journal Title: J. Biochem. Volume: 161 Pages: 27-35
  • DOI: 10.1093/jb/mvw069
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] LDL switches the LRP6 internalization route from flotillin dependent to clathrin dependent in hepatic cells. (2017)
  • Author(s): Yamamoto Hideki、Umeda Daisuke、Matsumoto Shinji、Kikuchi Akira
  • Journal Title: J. Cell Sci. Volume: 130 Pages: 3542-3556
  • DOI: 10.1242/jcs.202135
  • Peer Reviewed
• [Journal Article] The WNT/MYB pathway suppresses KIT expression to control the timing of salivary proacinar differentiation and duct formation. (2016)
  • Author(s): Matsumoto, S., Kurimoto, T., Taketo, M., Fujii, S., and Kikuchi, A.
  • Journal Title: Development. Volume: 143 Pages: 2311-2324
  • DOI: 10.1242/dev.134486
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Prickle1 promotes focal adhesion disassembly in cooperation with CLASP-LL5β complex in migrating cells. (2016)
  • Author(s): Lim, BC., Matsumoto, S., Yamamoto, H., Mizuno, H., Kikuta, J., Ishii, M., and Kikuchi, A.
  • Journal Title: J Cell Sci. Volume: 129 Pages: 3115-3129
  • DOI: 10.1242/jcs.185439
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Wnt5a-Ror2 axis promotes the signaling circuit between interleukin-12 and interferon-γ in colitis. (2015)
  • Author(s): Sato, A., Kayama, H., Shojima, K., Matsumoto, S., Koyama, H., Minami, Y., Nojima, S., Morii, E., Honda, H., Takeda, K., Kikuchi, A.
  • Journal Title: Scientific Rep. Volume: 5 Pages: 10536-10536
  • DOI: 10.1038/srep10536
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The P2Y2 receptor promotes Wnt3a- and EGF-induced epithelial tubular formation by IEC6 cells by binding to integrins (2015)
  • Author(s): Ibuka, S., Matsumoto, S., Fujii, S., Kikuchi, A.
  • Journal Title: Journal of Cell Science Volume: 128(11) Pages: 2156-2168
  • DOI: 10.1242/jcs.169060
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Basolateral secretion of Wnt5a in polarized epithelial cells is required for apical lumen formation (2015)
  • Author(s): Yamamoto, H., Awada, C., Matsumoto, S., Kaneiwa, T., Sugimoto, T., Takao, T., and Kikuchi
  • Journal Title: J. Cell Sci. Volume: 128 Pages: 1051-1063
  • DOI: 10.1242/jcs.163683
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 唾液腺におけるWntシグナル依存性新規前駆細胞の同定と機能解析 (2018)
  • Author(s): 松本真司
  • Organizer: 第60回歯科基礎医学会学術大会
• [Presentation] 唾液腺におけるWntシグナル依存的新規前駆細胞の同定と機能解析 (2018)
  • Author(s): 松本真司
  • Organizer: 第91回生化学会大会
• [Presentation] WntとKITシグナルの活性化バランスによる唾液腺の形づくりと機能獲得過程の制御 (2016)
  • Author(s): 松本真司
  • Organizer: 歯科基礎医学会
  • Place of Presentation: 札幌コンベンションセンター
• [Presentation] Wnt/β-catenin signaling regulates morphogenesis of embryonic salivary gland through the optimal control of end bud cell acinar formation (2015)
  • Author(s): 松本真司
  • Organizer: 第38回分子生物学会
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-02
• [Remarks] 大阪大学医学系研究科 分子病態生化学ホームページ
  • URL: http://www.med.osaka-u.ac.jp/pub/molbiobc/
• [Remarks] 大阪大学医学系研究科分子病態生化学
  • URL: http://www.med.osaka-u.ac.jp/pub/molbiobc/
• [Remarks] 大阪大学医学研究科分子病態生化学
  • URL: http://www.med.osaka-u.ac.jp/pub/molbiobc/index.html
• [Remarks] 大阪大学 分子病態生化学
  • URL: http://www.med.osaka-u.ac.jp/pub/molbiobc/
• [Remarks] 新学術領域研究 上皮管腔組織形成
  • URL: http://www.med.osaka-u.ac.jp/pub/molbiobc/tubulology/