1. Cell Biology
  2. Developmental Biology

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
https://doi.org/10.7554/eLife.77257
Share this article
Cite this article
  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
  2. Download BibTeX
  3. Download .RIS

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.

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

  • 1,345
    views
  • 264
    downloads
  • 10
    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 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

Categories and tags

Research organism

Further reading

    1. Cell Biology
    2. Neuroscience

    A neurotrophin functioning with a Toll regulates structural plasticity in a dopaminergic circuit

    Jun Sun, Francisca Rojo-Cortes ... Alicia Hidalgo
    Research Article

    Experience shapes the brain as neural circuits can be modified by neural stimulation or the lack of it. The molecular mechanisms underlying structural circuit plasticity and how plasticity modifies behaviour are poorly understood. Subjective experience requires dopamine, a neuromodulator that assigns a value to stimuli, and it also controls behaviour, including locomotion, learning, and memory. In Drosophila, Toll receptors are ideally placed to translate experience into structural brain change. Toll-6 is expressed in dopaminergic neurons (DANs), raising the intriguing possibility that Toll-6 could regulate structural plasticity in dopaminergic circuits. Drosophila neurotrophin-2 (DNT-2) is the ligand for Toll-6 and Kek-6, but whether it is required for circuit structural plasticity was unknown. Here, we show that DNT-2-expressing neurons connect with DANs, and they modulate each other. Loss of function for DNT-2 or its receptors Toll-6 and kinase-less Trk-like kek-6 caused DAN and synapse loss, impaired dendrite growth and connectivity, decreased synaptic sites, and caused locomotion deficits. In contrast, over-expressed DNT-2 increased DAN cell number, dendrite complexity, and promoted synaptogenesis. Neuronal activity modified DNT-2, increased synaptogenesis in DNT-2-positive neurons and DANs, and over-expression of DNT-2 did too. Altering the levels of DNT-2 or Toll-6 also modified dopamine-dependent behaviours, including locomotion and long-term memory. To conclude, a feedback loop involving dopamine and DNT-2 highlighted the circuits engaged, and DNT-2 with Toll-6 and Kek-6 induced structural plasticity in this circuit modifying brain function and behaviour.

    1. Cell Biology

    Inclusive, exclusive and hierarchical atlas of NFATc1+/PDGFR-α+ cells in dental and periodontal mesenchyme

    Xue Yang, Chuyi Han ... Fanyuan Yu
    Research Article

    Platelet-derived growth factor receptor alpha (PDGFR-α) activity is crucial in the process of dental and periodontal mesenchyme regeneration facilitated by autologous platelet concentrates (APCs), such as platelet-rich fibrin (PRF), platelet-rich plasma (PRP) and concentrated growth factors (CGF), as well as by recombinant PDGF drugs. However, it is largely unclear about the physiological patterns and cellular fate determinations of PDGFR-α+ cells in the homeostasis maintaining of adult dental and periodontal mesenchyme. We previously identified NFATc1 expressing PDGFR-α+ cells as a subtype of skeletal stem cells (SSCs) in limb bone in mice, but their roles in dental and periodontal remain unexplored. To this end, in the present study we investigated the spatiotemporal atlas of NFATc1+ and PDGFR-α+ cells residing in dental and periodontal mesenchyme in mice, their capacity for progeny cell generation, and their inclusive, exclusive and hierarchical relations in homeostasis. We utilized CRISPR/Cas9-mediated gene editing to generate two dual recombination systems, which were Cre-loxP and Dre-rox combined intersectional and exclusive reporters respectively, to concurrently demonstrate the inclusive, exclusive, and hierarchical distributions of NFATc1+ and PDGFR-α+ cells and their lineage commitment. By employing the state-of-the-art transgenic lineage tracing techniques in cooperating with tissue clearing-based advanced imaging and three-dimensional slices reconstruction, we systematically mapped the distribution atlas of NFATc1+ and PDGFR-α+ cells in dental and periodontal mesenchyme and tracked their in vivo fate trajectories in mice. Our findings extend current understanding of NFATc1+ and PDGFR-α+ cells in dental and periodontal mesenchyme homeostasis, and furthermore enhance our comprehension of their sustained therapeutic impact for future clinical investigations.

    1. Cell Biology
    2. Genetics and Genomics

    Full-length direct RNA sequencing uncovers stress granule-dependent RNA decay upon cellular stress

    Showkat Ahmad Dar, Sulochan Malla ... Manolis Maragkakis
    Research Article

    Cells react to stress by triggering response pathways, leading to extensive alterations in the transcriptome to restore cellular homeostasis. The role of RNA metabolism in shaping the cellular response to stress is vital, yet the global changes in RNA stability under these conditions remain unclear. In this work, we employ direct RNA sequencing with nanopores, enhanced by 5ʹ end adapter ligation, to comprehensively interrogate the human transcriptome at single-molecule and -nucleotide resolution. By developing a statistical framework to identify robust RNA length variations in nanopore data, we find that cellular stress induces prevalent 5ʹ end RNA decay that is coupled to translation and ribosome occupancy. Unlike typical RNA decay models in normal conditions, we show that stress-induced RNA decay is dependent on XRN1 but does not depend on deadenylation or decapping. We observed that RNAs undergoing decay are predominantly enriched in the stress granule transcriptome while inhibition of stress granule formation via genetic ablation of G3BP1 and G3BP2 rescues RNA length. Our findings reveal RNA decay as a key component of RNA metabolism upon cellular stress that is dependent on stress granule formation.