IADR Abstract Archives
The Role of Discoidin Domain Receptor 2 in Craniofacial Morphogenesis
Objectives: Discoidin domain receptor 2 (DDR2), a receptor tyrosine kinase activated by fibrillar collagen, is essential for skeletal development. In humans, mutations in DDR2 gene cause spondylo-meta-epiphyseal dysplasia (SMED), a rare, autosomal recessive disorder characterized by disproportionate short stature, short limbs and craniofacial anomalies. In addition to dwarfism and major defects in bone formation in the axial and appendicular skeleton, DDR2-deficient mice have distinct skull abnormalities including short snout, eye protrusions and shortened cranial length. The shortened skull phenotype suggests that DDR2 regulates craniofacial morphogenesis. However, little is known about the role of DDR2 in craniofacial development. Purpose of this study is to determine and characterize the role of DDR2 in cranial morphogenesis using loss of function genetic studies.
Methods: Ddr2 slie/slie mice used in our studies contain a spontaneous 150 kb deletion in the Ddr2 locus to produce an effective null. We analyzed mutant and control mice at P1, P14, and 3 months postnatally.
Results: LacZ staining of newborn calvariae from Ddr2-lacZ knock-in mice showed β gal activity in suture regions. We found that at P1, DDR2-mutant mice showed defective ossification compared with wild type littermates, as analyzed by micro CT. Two week-old, DDR2-deficient mice also had strikingly wide sutures, in particular posterior frontal (PF) sutures, which normally start to close around this time. PF sutures remained open until 3 months of age (last time point analyzed), suggesting the requirement of DDR2 in normal suture closure. In vitro analysis showed that DDR2 knockout causes a significant reduction in the proliferation and mineralization of calvarial-derived osteoblasts, both events being important during calvarial osteogenesis.
Conclusions: Together, these findings suggest a role for DDR2 signaling in intramembranous bone formation and calvarial suture closure via actions on osteoblast proliferation and differentiation. Our results also emphasize the importance of identifying etiology of human genetic diseases causing defective cranial morphogenesis
Methods: Ddr2 slie/slie mice used in our studies contain a spontaneous 150 kb deletion in the Ddr2 locus to produce an effective null. We analyzed mutant and control mice at P1, P14, and 3 months postnatally.
Results: LacZ staining of newborn calvariae from Ddr2-lacZ knock-in mice showed β gal activity in suture regions. We found that at P1, DDR2-mutant mice showed defective ossification compared with wild type littermates, as analyzed by micro CT. Two week-old, DDR2-deficient mice also had strikingly wide sutures, in particular posterior frontal (PF) sutures, which normally start to close around this time. PF sutures remained open until 3 months of age (last time point analyzed), suggesting the requirement of DDR2 in normal suture closure. In vitro analysis showed that DDR2 knockout causes a significant reduction in the proliferation and mineralization of calvarial-derived osteoblasts, both events being important during calvarial osteogenesis.
Conclusions: Together, these findings suggest a role for DDR2 signaling in intramembranous bone formation and calvarial suture closure via actions on osteoblast proliferation and differentiation. Our results also emphasize the importance of identifying etiology of human genetic diseases causing defective cranial morphogenesis
