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

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 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.

Cranial Base Synchondrosis: Chondrocytes at the Hub

“…In mice, Ddr2 is expressed in a gradient fashion in the long bone growth plate, with highest levels in the resting zone and lowest in the hypertrophic zone [113]. In the cranial base synchondroses, a similar expression gradient is observed [114]. Lineage tracing using a tamoxifen-inducible Ddr2-creER line showed that Ddr2-labeled cells are present in the cranial sutures and the resting and proliferating zones of the ISS and SOS, which could then differentiate into hypertrophic chondrocytes, osteoblasts and osteocytes, supporting the concept that Ddr2 is expressed by skeletal progenitors.…”

“…Ddr2-deficient mice display craniofacial abnormalities, including significant reductions in the lengths of the anterior and posterior cranial base and reduced mineralization of the frontal suture. Defects in cranial base length were related to reduced proliferation in both ISS and SOS chondrocytes in the absence of altered apoptosis or reduced osteoblast differentiation [ 114 ]. Interestingly, the reduced cranial base growth was associated with widening of synchondroses, loss of chondrocyte polarity and abnormal distribution of ColX and Col2 , suggesting a role for Ddr2 in regulating fibrillogenesis and extracellular matrix distribution.…”