Functions of regulators for Notch signaling, almondex/TM2D3

• Project/Area Number: 16K08577
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: International University of Health and Welfare (2017-2019); Chiba University (2016)
• Principal Investigator: Motoo Kitagawa 国際医療福祉大学, 医学部, 教授 (40262026)
• Co-Investigator(Kenkyū-buntansha): 増田 渉 埼玉医科大学, 医学部, 助教 (00623464)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: Notchシグナル / TM2D3 / almondex / Notch / シグナル伝達 / 発生・分化

Outline of Final Research Achievements

We have examined mouse Tm2d3 and its Drosophila homolog almondex (amx) by using their respective deficient mutant animals.
Murine Tm2d3-deficient cultured cells were found to have decreased surface expression of both Notch1 and Notch2 as compared with the wild type cells. In the ventral presumptive mesodermal cells of early Drosophila embryos, Notch and its ligand Delta interact, are endocytosed, and co-localize in intracellular vesicles. In contrast, such vesicles were scarcely observed in the amx-deficient mutants.
Based on these results, it is concluded that TM2D3/amx positively regulates surface expression of Notch receptors to interact with their ligands.

Academic Significance and Societal Importance of the Research Achievements

本研究は、これまで不明であったTM2D3とalmondexの生化学的、細胞生物学的な機能を初めて明らかにしたものである。Notchシグナルの異常は各種悪性腫瘍、遺伝性疾患の原因であることが知られているが、本研究の成果によって今後こうした問題の理解が深まり、さらに解決の手がかりが得られることを期待する。またヒトにおいて、TM2D3のある遺伝子多型が晩期発症型アルツハイマー病の発症危険率を約7.5倍上昇させ、さらに発症年齢を約10年早めることが知られているが、本研究の成果が今後この機構を解明するために役立つことも期待する。

Research Products

• [Journal Article] Delta-like 1 and Delta-like 4 differently require their extracellular domains for triggering Notch signaling in mice (2020)
  • Author(s): Hirano Ken-ichi、Suganami Akiko、Tamura Yutaka、Yagita Hideo、Habu Sonoko、Kitagawa Motoo、Sato Takehito、Hozumi Katsuto
  • Journal Title: eLife Volume: 9
  • DOI: 10.7554/elife.50979
  • Peer Reviewed / Open Access
• [Journal Article] Maternal almondex, a neurogenic gene, is required for proper subcellular Notch distribution in early Drosophila embryogenesis. (2020)
  • Author(s): Das P., Salazar J. L., Li-Kroeger D., Yamamoto S., Nakamura M., Sasamura T., Inaki M., Masuda W., Kitagawa M., Yamakawa T., Matsuno K.
  • Journal Title: Development, Growth & Differentiation Volume: 62 Issue: 1 Pages: 80-93
  • DOI: 10.1111/dgd.12639
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TM2 domain containing 3（TM2D3）はNotch受容体 の細胞表面の発現を制御する (2019)
  • Author(s): 北川元生、増田渉、山川智子、安島理恵子、三宅克也、梅宮敏文、東和彦、田丸淳一、相賀裕美子、松野健治
  • Journal Title: 国際医療福祉大学学会誌 Volume: 24 Pages: 171-171
• [Journal Article] TM2 domain containing 3（TM2D3）によるNotch1 の活性化 (2018)
  • Author(s): 北川元生、増田渉、山川智子、安島理恵子、梅宮敏文、東和彦、田丸淳一、相賀裕美子、松野健治
  • Journal Title: 国際医療福祉大学学会誌 Volume: 23 Pages: 151-151
• [Journal Article] Regulation of striatal dopamine responsiveness by Notch/RBP-J signaling. (2017)
  • Author(s): Toritsuka M, Kimoto S, Muraki K, Kitagawa M, Kishimoto T, Sawa A, Tanigaki K.
  • Journal Title: Transl Psychiatry. Volume: 7 Issue: 3 Pages: e1049-e1049
  • DOI: 10.1038/tp.2017.21
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lipoid Pneumonia with Partial Anomalous Pulmonary Venous Return (2016)
  • Author(s): Fujita T., Terada J., Kitagawa M., Tatsumi K.
  • Journal Title: Internal Medicine Volume: 55 Issue: 10 Pages: 1399-1400
  • DOI: 10.2169/internalmedicine.55.6392
  • NAID: 130005151163
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] Olfactory Sensory Neurons Control Dendritic Complexity of Mitral Cells via Notch Signaling. (2016)
  • Author(s): Yuko Muroyama, Atsushi Baba, Motoo Kitagawa, Tetsuichiro Saito
  • Journal Title: PLOS Genetics Volume: 12(12) Issue: 12 Pages: e1006514-e1006514
  • DOI: 10.1371/journal.pgen.1006514
  • Peer Reviewed / Open Access
• [Presentation] TM2 domain containing 3, a mammalian homologue of Drosophila neurogenic gene product Almondex, regulates surface presentation of Notch receptors. (2019)
  • Author(s): Masuda W., Yamakawa T., Ajima R., Miyake K., Umemiya T., Azuma K., Tamaru J.-i., Kiso M., Saga Y., Matsuno K., Kitagawa M.
  • Organizer: The Notch Meeting XI
  • Int'l Joint Research
• [Presentation] Transmembrane 2 domain-containing 3（TM2D3）はNotch受容体 の細胞表面の発現を制御する (2019)
  • Author(s): 北川元生
  • Organizer: 第92回日本生化学会大会
• [Presentation] Transmembrane 2 domain containing 3（TM2D3）はNotch受容体 の細胞表面の発現を制御する (2019)
  • Author(s): 北川元生、増田渉、山川智子、安島理恵子、三宅克也、梅宮敏文、東和彦、田丸淳一、相賀裕美子、松野健治
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] TM2 domain containing 3（TM2D3）はNotch受容体 の細胞表面の発現を制御する (2019)
  • Author(s): 北川元生、増田渉、山川智子、安島理恵子、三宅克也、梅宮敏文、東和彦、田丸淳一、相賀裕美子、松野健治
  • Organizer: 第9回国際医療福祉大学学会学術大会
• [Presentation] TM2 domain containing 3（TM2D3）によるNotch1 の活性化 (2018)
  • Author(s): 北川元生
  • Organizer: 第8回国際医療福祉大学学会学術大会
• [Presentation] TM2 domain containing 3, a mammalian homologue of Drosophila neurogenic gene product Almondex, activates Notch1. (2017)
  • Author(s): Motoo Kitagawa
  • Organizer: The Notch Meeting X
  • Int'l Joint Research
• [Presentation] TM2 domain containing 3, a possible mammalian homologue of Drosophila neurogenic gene product Almondex, activates Notch1 (2016)
  • Author(s): Masuda W.
  • Organizer: Notch研究会
  • Place of Presentation: 国立遺伝学研究所（静岡県三島市）
  • Year and Date: 2016-10-05