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

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    Evaluation Summary:

    The authors report that discoidin domain receptor 2 (DDR2), a non-integrin collagen receptor, is required in Gli1+ cells for the development of the craniofacial skeleton. It is known that mutations in DDR2 are associated with craniofacial abnormalities, such as midface hypoplasia and open fontanels. This paper is of potential interest to craniofacial skeletal developmental researchers. While the data quality is high, the paper helps to confirm what has been recently published by the same authors.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

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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.

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  1. Author Response

    Reviewer #1 (Public Review):

    The authors characterized the expression of DDR2 in the developing craniofacial skeleton. The authors showed that Ddr2-deficient mice exhibited 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. The histological studies are well done. However, the studies as shown in this manuscript do not provide cellular and molecular mechanisms beyond what is already known, particularly beyond what the authors have already published in a similar study in Bone Research (Mohamed et al., 2022 Feb 9;10(1):11). With the same Cre lines and analytic approaches, the authors already showed in the Bone Research paper that Ddr2 in the Gli1+ cells is required …

  2. Evaluation Summary:

    The authors report that discoidin domain receptor 2 (DDR2), a non-integrin collagen receptor, is required in Gli1+ cells for the development of the craniofacial skeleton. It is known that mutations in DDR2 are associated with craniofacial abnormalities, such as midface hypoplasia and open fontanels. This paper is of potential interest to craniofacial skeletal developmental researchers. While the data quality is high, the paper helps to confirm what has been recently published by the same authors.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

  3. Reviewer #1 (Public Review):

    The authors characterized the expression of DDR2 in the developing craniofacial skeleton. The authors showed that Ddr2-deficient mice exhibited 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. The histological studies are well done. However, the studies as shown in this manuscript do not provide cellular and molecular mechanisms beyond what is already known, particularly beyond what the authors have already published in a similar study in Bone Research (Mohamed et al., 2022 Feb 9;10(1):11). With the same Cre lines and analytic approaches, the authors already showed in the Bone Research paper that Ddr2 in the Gli1+ cells is required for chondrocyte …

  4. Reviewer #2 (Public Review):

    DDR2 is a collagen-binding receptor that is required for proper skull development. Ddr2 loss-of-function in humans is associated with the developmental disease spondylo-meta-epiphyseal dysplasia (SMED). Here, the authors aim to elucidate the role of DDR2 in skull development. In this work, the role of DDR2 in skull and face development is studied in mice, which exhibit SMED-like symptoms in the absence of Ddr2. Histological studies showed that Ddr2 knockout disrupts organization and proper differentiation within progenitor-rich regions of the skull from which bone growth occurs. Histology and lineage tracing studies revealed that DDR-expressing cells in/around these zones 1) generally also express the proliferation regulator Gli1, and 2) eventually contribute to osteogenic and chondrogenic lineages. …

  5. Reviewer #3 (Public Review):

    From this work, the authors investigated a number of parameters in order to profoundly understand and demonstrate the vital role of ongoing interaction between components of extracellular matrix and particular stem cells to induce normal Craniofacial development. Thus, there was a focus on the genetic manipulation (knockout) impact of molecules behind the above-mentioned interaction, and on determining how such modification would be reflected on skull bone morphogenesis.

    Strengths and Weaknesses:

    • Using different animals' backgrounds in the same experiment might impact work outcomes.

    • Better to have (ethical approval) at the beginning of the material and methods in separate paragraphs.

    • It is great that the authors precisely explain all the measurements.

    • Supplementary file to have details of used …