The collagen receptor, discoidin domain receptor 2, functions in Gli1-positive skeletal progenitors and chondrocytes to control bone development

Mohamed, Fatma F.; Ge, Chunxi; Cowling, Randy T.; Lucas, Daniel; Hallett, Shawn A; Ono, Noriaki; Binrayes, Abdulaziz; Greenberg, Barry; Franceschi, Renny T.

doi:10.1038/s41413-021-00182-w

Cited by 18 publications

(35 citation statements)

References 65 publications

(82 reference statements)

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“…Significant similarities and differences are apparent when results of the present study are compared with our previous work on Ddr2 functions in the appendicular skeleton 32 . At both sites, Ddr2 was localized to resting and proliferative zone cartilage of synchondroses or long bone growth plates, respectively, where co-localization with the Hh intermediate, Gli1, was observed.…”

Section: Discussionsupporting

confidence: 66%

“…In the cranial vault, Ddr2 deficiency inhibited frontal suture formation and reduced frontal bone thickness. In contrast, Ddr2 deficiency had little effect on thickness of tibial cortical bone, which also forms through an intramembranous process 32 . The basis for these differences is not clear.…”

Section: Discussionmentioning

confidence: 83%

“…While determining DDR2 regulation of various aspects of collagen fibrillogenesis is beyond the goal of this study, our findings are in agreement with previous studies showing abnormal collagen organization and/or crosslinking in Ddr2-deficient long bone growth plates, heart, postnatal testicular tissues and tumor-associated stroma. 32,[49][50][51] In addition, our previous characterization of Ddr2 function in tooth development showed atypical collagen fibers in periodontal ligaments surrounding tooth roots in Ddr2 slie/slie mice. 31 Most importantly, the altered distribution of cartilage matrix was also reported in a SMED, SL-AC patient.…”

Section: Discussionmentioning

confidence: 99%

“…Tamoxifen was administered as previously described. 32 To investigate the role of Ddr2 in craniofacial development, we generated conditional Col2a1-Cre, Gli1-Cre ERT , OC-Cre and Ai14: R26R-tdTomato mice was performed using PCR primers, as previously described. 35,36,61,62 The genotyping of Ddr2 slie/slie mice was performed using qRT-PCR with TaqMan probes on an ABI 7500 (Applied BioSystems).…”

Section: Micementioning

confidence: 99%

“…We recently described cell autonomous functions of Ddr2 in growth of the appendicular skeleton 32 . Preferential localization of DDR2 in GLI1-positive skeletal progenitor populations associated with resting/growth zone chondrocytes of the growth plate and bone marrow was demonstrated while conditional inactivation of Ddr2 in Gli1 -expressing cells and chondrocytes phenocopied the dwarf bone phenotype of globally Ddr2 -deficient mice.…”

Section: Introductionmentioning

confidence: 99%

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Control of Craniofacial Development by the Collagen Receptor, Discoidin Domain Receptor 2

Mohamed

Cowling

et al. 2022

Preprint

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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 discoidin domain receptor 2 (DDR2), a non-integrin collagen receptor, are associated with craniofacial abnormalities, such as midface hypoplasia and open fontanels. However, the exact role of DDR2 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. 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 Gli1+ skeletal progenitors and chondrocytes and suggest important functions in chondrocyte proliferation and orientation as well as ECM organization. These studies establish a cellular basis for regulation of craniofacial morphogenesis by this understudied collagen receptor.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Control of Craniofacial Development by the Collagen Receptor, Discoidin Domain Receptor 2

Mohamed

Cowling

et al. 2022

Preprint

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DDR2 signaling and mechanosensing orchestrate neuroblastoma cell fate through different transcriptome mechanisms

Vessella,

Xiang,

Xiao

et al. 2024

FEBS Open Bio

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The extracellular matrix (ECM) regulates carcinogenesis by interacting with cancer cells via cell surface receptors. Discoidin Domain Receptor 2 (DDR2) is a collagen‐activated receptor implicated in cell survival, growth, and differentiation. Dysregulated DDR2 expression has been identified in various cancer types, making it as a promising therapeutic target. Additionally, cancer cells exhibit mechanosensing abilities, detecting changes in ECM stiffness, which is particularly important for carcinogenesis given the observed ECM stiffening in numerous cancer types. Despite these, whether collagen‐activated DDR2 signaling and ECM stiffness‐induced mechanosensing exert similar effects on cancer cell behavior and whether they operate through analogous mechanisms remain elusive. To address these questions, we performed bulk RNA sequencing (RNA‐seq) on human SH‐SY5Y neuroblastoma cells cultured on collagen‐coated substrates. Our results show that DDR2 downregulation induces significant changes in the cell transcriptome, with changes in expression of 15% of the genome, specifically affecting the genes associated with cell division and differentiation. We validated the RNA‐seq results by showing that DDR2 knockdown redirects the cell fate from proliferation to senescence. Like DDR2 knockdown, increasing substrate stiffness diminishes cell proliferation. Surprisingly, RNA‐seq indicates that substrate stiffness has no detectable effect on the transcriptome. Furthermore, DDR2 knockdown influences cellular responses to substrate stiffness changes, highlighting a crosstalk between these two ECM‐induced signaling pathways. Based on our results, we propose that the ECM could activate DDR2 signaling and mechanosensing in cancer cells to orchestrate their cell fate through distinct mechanisms, with or without involving gene expression, thus providing novel mechanistic insights into cancer progression.

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Collagen receptors

Jansen,

Willumsen,

Karsdal

2024

Biochemistry of Collagens, Laminins and Elastin

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The collagen receptor, discoidin domain receptor 2, functions in Gli1-positive skeletal progenitors and chondrocytes to control bone development

Cited by 18 publications

References 65 publications

Control of Craniofacial Development by the Collagen Receptor, Discoidin Domain Receptor 2

Control of Craniofacial Development by the Collagen Receptor, Discoidin Domain Receptor 2

DDR2 signaling and mechanosensing orchestrate neuroblastoma cell fate through different transcriptome mechanisms

Collagen receptors

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