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 D 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 D 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 D 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.

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.

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.

Metrics

  • 1,394
    views
  • 268
    downloads
  • 11
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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 D 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

Further reading

    1. Cell Biology
    Yajun Zhai, Peiyi Liu ... Gongzheng Hu
    Research Article

    Discovering new strategies to combat the multidrug-resistant bacteria constitutes a major medical challenge of our time. Previously, artesunate (AS) has been reported to exert antibacterial enhancement activity in combination with β-lactam antibiotics via inhibition of the efflux pump AcrB. However, combination of AS and colistin (COL) revealed a weak synergistic effect against a limited number of strains, and few studies have further explored its possible mechanism of synergistic action. In this article, we found that AS and EDTA could strikingly enhance the antibacterial effects of COL against mcr-1- and mcr-1+ Salmonella strains either in vitro or in vivo, when used in triple combination. The excellent bacteriostatic effect was primarily related to the increased cell membrane damage, accumulation of toxic compounds and inhibition of MCR-1. The potential binding sites of AS to MCR-1 (THR283, SER284, and TYR287) were critical for its inhibition of MCR-1 activity. Additionally, we also demonstrated that the CheA of chemosensory system and virulence-related protein SpvD were critical for the bacteriostatic synergistic effects of the triple combination. Selectively targeting CheA, SpvD, or MCR using the natural compound AS could be further investigated as an attractive strategy for the treatment of Salmonella infection. Collectively, our work opens new avenues toward the potentiation of COL and reveals an alternative drug combination strategy to overcome COL-resistant bacterial infections.

    1. Cell Biology
    2. Genetics and Genomics
    Adam D Longhurst, Kyle Wang ... David P Toczyski
    Tools and Resources

    Progression through the G1 phase of the cell cycle is the most highly regulated step in cellular division. We employed a chemogenetic approach to discover novel cellular networks that regulate cell cycle progression. This approach uncovered functional clusters of genes that altered sensitivity of cells to inhibitors of the G1/S transition. Mutation of components of the Polycomb Repressor Complex 2 rescued proliferation inhibition caused by the CDK4/6 inhibitor palbociclib, but not to inhibitors of S phase or mitosis. In addition to its core catalytic subunits, mutation of the PRC2.1 accessory protein MTF2, but not the PRC2.2 protein JARID2, rendered cells resistant to palbociclib treatment. We found that PRC2.1 (MTF2), but not PRC2.2 (JARID2), was critical for promoting H3K27me3 deposition at CpG islands genome-wide and in promoters. This included the CpG islands in the promoter of the CDK4/6 cyclins CCND1 and CCND2, and loss of MTF2 lead to upregulation of both CCND1 and CCND2. Our results demonstrate a role for PRC2.1, but not PRC2.2, in antagonizing G1 progression in a diversity of cell linages, including chronic myeloid leukemia (CML), breast cancer, and immortalized cell lines.