Delta-like 1 and Delta-like 4 differently require their extracellular domains for triggering Notch signaling in mice

  1. Ken-ichi Hirano
  2. Akiko Suganami
  3. Yutaka Tamura
  4. Hideo Yagita
  5. Sonoko Habu
  6. Motoo Kitagawa
  7. Takehito Sato
  8. Katsuto Hozumi  Is a corresponding author
  1. Tokai University School of Medicine, Japan
  2. Chiba University, Japan
  3. Juntendo University School of Medicine, Japan
  4. International University of Health and Welfare School of Medicine, Japan
  5. Tokai University, Japan

Abstract

Delta-like (Dll) 1 and Dll4 differently function as Notch ligands in a context-dependent manner. As these ligands share structural properties, the molecular basis for their functional difference is poorly understood. Here, we investigated the superiority of Dll4 over Dll1 with respect to induction of T cell development using a domain-swapping approach in mice. The DOS motif, shared by Notch ligands—except Dll4—contributes to enhancing the activity of Dll for signal transduction. The module at the N-terminus of Notch ligand (MNNL) of Dll4 is inherently advantageous over Dll1. Molecular dynamic simulation revealed that the loop structure in MNNL domain of Dll1 contains unique proline residues with limited range of motion. The Dll4 mutant with Dll1-derived proline residues showed reduced activity. These results suggest that the loop structure—present within the MNNL domain—with a wide range of motion ensures the superiority of Dll4 and uniquely contributes to the triggering of Notch signaling.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 2, 3, 4 and 6.

The following previously published data sets were used

Article and author information

Author details

  1. Ken-ichi Hirano

    Department of Immunology, Tokai University School of Medicine, Isehara, Japan
    Competing interests
    The authors declare that no competing interests exist.
  2. Akiko Suganami

    Department of Bioinformatics, Chiba University, Chiba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  3. Yutaka Tamura

    Department of Bioinformatics, Chiba University, Chiba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  4. Hideo Yagita

    Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  5. Sonoko Habu

    Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  6. Motoo Kitagawa

    Department of Biochemistry, International University of Health and Welfare School of Medicine, Narita, Japan
    Competing interests
    The authors declare that no competing interests exist.
  7. Takehito Sato

    Department of Immunology, Tokai University, Isehara, Japan
    Competing interests
    The authors declare that no competing interests exist.
  8. Katsuto Hozumi

    Department of Immunology, Tokai University, Isehara, Japan
    For correspondence
    hozumi@is.icc.u-tokai.ac.jp
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7685-6927

Funding

Japan Society for the Promotion of Science (16K08848)

  • Katsuto Hozumi

Ministry of Education, Culture, Sports, Science, and Technology (22021040)

  • Katsuto Hozumi

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Tomohiro Kurosaki, Osaka University, Japan

Ethics

Animal experimentation: Animal experimentation: All animal experiments were performed under protocols approved by the Animal Experimentation Committee of Tokai University (Approval No.: 165015, 171002, 182026, 193040), which is further monitored by the Animal Experimentation Evaluation Committee of Tokai University with researcher for Humanities/Sociology and external expert.

Version history

  1. Received: August 9, 2019
  2. Accepted: January 9, 2020
  3. Accepted Manuscript published: January 14, 2020 (version 1)
  4. Accepted Manuscript updated: January 16, 2020 (version 2)
  5. Version of Record published: January 28, 2020 (version 3)

Copyright

© 2020, Hirano et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ken-ichi Hirano
  2. Akiko Suganami
  3. Yutaka Tamura
  4. Hideo Yagita
  5. Sonoko Habu
  6. Motoo Kitagawa
  7. Takehito Sato
  8. Katsuto Hozumi
(2020)
Delta-like 1 and Delta-like 4 differently require their extracellular domains for triggering Notch signaling in mice
eLife 9:e50979.
https://doi.org/10.7554/eLife.50979

Share this article

https://doi.org/10.7554/eLife.50979

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