Control of craniofacial development by the collagen receptor, discoidin domain receptor 2

  1. Fatma F Mohamed
  2. Chunxi Ge
  3. Shawn A Hallett
  4. Alec C Bancroft
  5. Randy T Cowling
  6. Noriaki Ono
  7. Abdul-Aziz Binrayes
  8. Barry Greenberg
  9. Benjamin Levi
  10. Vesa M Kaartinen
  11. Renny T Franceschi  Is a corresponding author
  1. University of Michigan-Ann Arbor, United States
  2. The University of Texas Southwestern Medical Center, United States
  3. University of California, San Diego, United States
  4. The University of Texas Health Science Center at Houston, United States
  5. King Saud University, Saudi Arabia

Abstract

Development of the craniofacial skeleton requires interactions between progenitor cells and the collagen-rich extracellular matrix (ECM). The mediators of these interactions are not well-defined. Mutations in the discoidin domain receptor 2 gene (DDR2), which encodes a non-integrin collagen receptor, are associated with human craniofacial abnormalities, such as midface hypoplasia and open fontanels. However, the exact role of this gene in craniofacial morphogenesis is not known. As will be shown, Ddr2-deficient mice exhibit defects in craniofacial bones including impaired calvarial growth and frontal suture formation, cranial base hypoplasia due to aberrant chondrogenesis and delayed ossification at growth plate synchondroses. These defects were associated with abnormal collagen fibril organization, chondrocyte proliferation and polarization. As established by localization and lineage tracing studies, Ddr2 is expressed in progenitor cell-enriched craniofacial regions including sutures and synchondrosis resting zone cartilage, overlapping with GLI1+ cells, and contributing to chondrogenic and osteogenic lineages during skull growth. Tissue-specific knockouts further established the requirement for Ddr2 in GLI+ skeletal progenitors and chondrocytes. These studies establish a cellular basis for regulation of craniofacial morphogenesis by this understudied collagen receptor and suggest that DDR2 is necessary for proper collagen organization, chondrocyte proliferation and orientation.

Data availability

All data generated or analysed during this study are included in the manuscript and source data files

Article and author information

Author details

  1. Fatma F Mohamed

    Department of Periodontics and Oral Medicine, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Chunxi Ge

    Department of Periodontics and Oral Medicine, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Shawn A Hallett

    Department of Periodontics and Oral Medicine, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1472-7502
  4. Alec C Bancroft

    Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Randy T Cowling

    Division of Cardiovascular Medicine, University of California, San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Noriaki Ono

    Department of Diagnostic and Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3771-8230
  7. Abdul-Aziz Binrayes

    Department of Prosthetic Dental Sciences, King Saud University, Riyadh, Saudi Arabia
    Competing interests
    The authors declare that no competing interests exist.
  8. Barry Greenberg

    Division of Cardiovascular Medicine, University of California, San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Benjamin Levi

    Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Vesa M Kaartinen

    Department of Biologic and Materials Science, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Renny T Franceschi

    Department of Periodontics and Oral Medicine, University of Michigan-Ann Arbor, Ann Arbor, United States
    For correspondence
    rennyf@umich.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1405-2541

Funding

National Institute of Dental and Craniofacial Research (R01DE11723)

  • Renny T Franceschi

National Institute of Dental and Craniofacial Research (R21DE029012)

  • Renny T Franceschi

National Institute of Dental and Craniofacial Research (R01DE029465)

  • Renny T Franceschi

U.S. Department of Defense (PR190899)

  • Renny T Franceschi

National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR078324)

  • Benjamin Levi

National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR069620)

  • Renny T Franceschi

Ministry of Higher Education and Scientific Research

  • Fatma F Mohamed

King Saud University

  • Abdul-Aziz Binrayes

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

Reviewing Editor

  1. Yi-Ping Li, Tulane University, United States

Ethics

Animal experimentation: This study was performed in strict compliance with the Guidelines for the Care and Use of Animals for Scientific Research. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (PRO9305, PRO10975) of the University of Michigan.

Version history

  1. Received: January 21, 2022
  2. Preprint posted: February 3, 2022 (view preprint)
  3. Accepted: January 18, 2023
  4. Accepted Manuscript published: January 19, 2023 (version 1)
  5. Accepted Manuscript updated: January 24, 2023 (version 2)
  6. Version of Record published: February 28, 2023 (version 3)
  7. Version of Record updated: October 30, 2023 (version 4)

Copyright

© 2023, Mohamed 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. Fatma F Mohamed
  2. Chunxi Ge
  3. Shawn A Hallett
  4. Alec C Bancroft
  5. Randy T Cowling
  6. Noriaki Ono
  7. Abdul-Aziz Binrayes
  8. Barry Greenberg
  9. Benjamin Levi
  10. Vesa M Kaartinen
  11. Renny T Franceschi
(2023)
Control of craniofacial development by the collagen receptor, discoidin domain receptor 2
eLife 12:e77257.
https://doi.org/10.7554/eLife.77257

Share this article

https://doi.org/10.7554/eLife.77257

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