Origin of the adult epithelial stem cell in the Xenopus laevis intestine and the role of Notch signaling in the stem cell regulation

• Project/Area Number: 25440160
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Morphology/Structure
• Research Institution: Nippon Medical School
• Principal Investigator: Hasebe Takashi 日本医科大学, 医学部, 准教授 (70329027)
• Research Collaborator: BUCHHOLZ Daniel R. シンシナティ大学, 生物科学科, 准教授
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2016: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 上皮幹細胞 / 消化管 / 甲状腺ホルモン / 両生類 / 変態 / Notchシグナル経路 / 幹細胞 / Notchシグナル / Cre-Loxシステム / Notch

Outline of Final Research Achievements

In the small intestine of Xenopus laevis during metamorphosis, which is caused by thyroid hormone (TH), most of the larval epithelial cells are removed by apoptosis whereas some cells dedifferentiate into the adult epithelial stem cells. They actively proliferate and differentiate to form the adult epithelium.
We found that during this intestinal remodeling, Notch signaling pathway is activated by TH and that inhibition of this pathway inhibits TH-induced up-regulation of Notch response gene and, more importantly, LGR5, an adult intestinal stem cell marker gene. In addition, inhibition of Notch suppressed differentiation of the stem cells into the absorptive epithelial cells, but facilitated their differentiation into the secretory epithelial cells. Our results suggest that Notch signaling plays important roles in the intestinal remodeling.

Research Products

• [Journal Article] Thyroid hormone-induced activation of Notch signaling is required for adult intestinal stem cell development during Xenopus laevis metamorphosis (2017)
  • Author(s): Hasebe T, Fujimoto K, Kajita M, Fu L, Shi Y-B, Ishizuya-Oka A
  • Journal Title: Stem Cells Volume: 35 Issue: 4 Pages: 1028-1039
  • DOI: 10.1002/stem.2544
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Thyroid hormone activates Wnt/beta-catenin signaling involved in adult epithelial development during intestinal remodeling in Xenopus laevis (2016)
  • Author(s): Hasebe T, Fujimoto K, Kajita M, Ishizuya-Oka A
  • Journal Title: Cell Tissue Res Volume: 365 Issue: 2 Pages: 309-318
  • DOI: 10.1007/s00441-016-2396-8
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A requirement for hedgehog signaling in thyroid hormone-induced postembryonic intestinal remodeling. (2015)
  • Author(s): Wen, L., Hasebe, T., Miller T.C., Ishizuya-Oka, A., Shi Y.-B.
  • Journal Title: Cell & Bioscience Volume: 5 Issue: 1 Pages: 1-12
  • DOI: 10.1186/s13578-015-0004-3
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of androgen receptor in sex determination in an amphibian species (2014)
  • Author(s): Fujii, J., Kodama, M., Oike, A., Matsuo, Y., Min, M.S., Hasebe, T., Ishizuya-Oka, A., Kawakami, K., and Nakamura, M.
  • Journal Title: PLoS One Volume: 9 Issue: 5 Pages: e93655-e93655
  • DOI: 10.1371/journal.pone.0093655
  • Peer Reviewed / Open Access
• [Journal Article] Thyroid hormone-regulated Wnt5a/Ror2 signaling is essential for dedifferentiation of larval epithelial cells into adult stem cells in the Xenopus laevis intestine. (2014)
  • Author(s): Ishizuya-Oka, A., Kajita M., Hasebe, T.
  • Journal Title: PLoS One Volume: 9 Issue: 9 Pages: e107611-e107611
  • DOI: 10.1371/journal.pone.0107611
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Expression profiling of intestinal tissues implicates novel genes and pathways essential for adult stem cell development (2013)
  • Author(s): Sun, G., Heimeier R. A., Fu, L., Hasebe, T., Das, B., Ishizuya-Oka, A., Shi, Y.-B.
  • Journal Title: Endocrinology Volume: 154 Issue: 11 Pages: 4396-4407
  • DOI: 10.1210/en.2013-1432
  • Peer Reviewed
• [Journal Article] Thyroid hormone-induced cell-cell interactions in the development of adult intestinal stem cells (2013)
  • Author(s): Hasebe, T., Liezhen Fu, L., Thomas C. Miller, T. C., Zhang, Y., Shi Y.-B., Ishizuya-Oka., A.
  • Journal Title: Cell & Bioscience Volume: 3 Issue: 1 Pages: 18-18
  • DOI: 10.1186/2045-3701-3-18
  • Peer Reviewed
• [Journal Article] Tissue-specific upregulation of MDS/EVI gene transcripts in the intestine by thyroid hormone during Xenopus metamorphosis (2013)
  • Author(s): Miller TC, Sun G, Hasebe T, Fu L, Heimeier RA, Das B, Ishizuya-Oka A, Shi Y-B
  • Journal Title: PLoS One Volume: 8 Issue: 1 Pages: e55585-e55585
  • DOI: 10.1371/journal.pone.0055585
  • Peer Reviewed
• [Presentation] Thyroid hormone-induced activation of Notch signaling is required for intestinal remodeling during Xenopus laevis metamorphosis (2016)
  • Author(s): Hasebe T, Fujimoto K, Kajita M, Fu L, Shi Y-B, Ishizuya-Oka A
  • Organizer: The joint meeting of the 22nd International Congress of Zoology and the 87th Meeting of the Zoological Society of Japan
  • Place of Presentation: 沖縄
  • Year and Date: 2016-11-17
  • Int'l Joint Research
• [Presentation] アフリカツメガエルの消化管再構築においてWntシグナルは甲状腺ホルモンにより活性化され成体型上皮の発生に関与する (2016)
  • Author(s): 長谷部孝、藤本健太、岡敦子
  • Organizer: 日本組織細胞化学会総会・学術集会（第57回)
  • Place of Presentation: 東京
  • Year and Date: 2016-09-03
• [Presentation] アフリカツメガエルの消化管再構築におけるヒアルロン酸合成酵素の遺伝子発現解析 (2016)
  • Author(s): 藤本健太、長谷部孝、梶田満子、岡 敦子
  • Organizer: 日本分子生物学会年会（第39回）
  • Place of Presentation: 横浜
• [Presentation] ツメガエル変態期の消化管再構築におけるNotchシグナルの役割：DLL1とDLL2の発現解析 (2015)
  • Author(s): 長谷部孝、梶田満子、岡敦子
  • Organizer: 日本動物学会第86回大会
  • Place of Presentation: 新潟
  • Year and Date: 2015-09-19
• [Presentation] Notch signaling-dependent gene expression of Hairy1 and Hairy2b during adult stencil development in the Xenopus laevis intestine (2014)
  • Author(s): Hasebe, T., Kajita, M., Ishizuya-Oka, A.
  • Organizer: The 8th International Symposium on Amphibian and Reptilian Endocrinology and Neurobiology
  • Place of Presentation: 岡崎
  • Year and Date: 2014-11-07
  • Invited
• [Presentation] アフリカツメガエル変態期の消化管再構築における JaggedとJagged 2 の発現解析 (2014)
  • Author(s): 関本篤人、福永悦也、梶田満子、長谷部 孝、岡敦子
  • Organizer: 日本動物学会第85回大会
  • Place of Presentation: 仙台
  • Year and Date: 2014-09-13
• [Presentation] アフリカツメガエル変態期の小腸におけるHairy1とHairy2bの発現はNotchシグナル依存的である (2013)
  • Author(s): 長谷部孝、梶田満子、岡敦子
  • Organizer: 日本動物学会第84回大会
  • Place of Presentation: 岡山
• [Presentation] アフリカツメガエル小腸上皮の脱分化機構: Wnt5a/Ror2シグナルの関与 (2013)
  • Author(s): 岡敦子、長谷部孝
  • Organizer: 日本動物学会第84回大会
  • Place of Presentation: 岡山
• [Presentation] アンドロゲンとその受容体はツチガエルの性を決める? (2013)
  • Author(s): 児玉万穂、藤井淳、松尾安希、長谷部孝、岡敦子、中村正久
  • Organizer: 日本動物学会第84回大会
  • Place of Presentation: 岡山
• [Remarks] 日本医科大学生物学教室
  • URL: http://www2.nms.ac.jp/nms/biology/Research.html
• [Remarks] Publications
  • URL: http://www.nms.ac.jp/nms/biology/Hasebe_publications.html
• [Remarks] Hasebe
  • URL: http://www.nms.ac.jp/nms/biology/Hasebe.html