ABSTRACT
The development and growth of the skull is controlled by cranial sutures, which serve as growth centers for osteogenesis by providing a pool of osteoprogenitors. These osteoprogenitors undergo intramembranous ossification by direct differentiation into osteoblasts, which synthesize the components of the extracellular bone matrix. A dysregulation of osteoblast differentiation can lead to premature fusion of sutures, resulting in an abnormal skull shape, a disease called craniosynostosis. Although several genes could be linked to craniosynostosis, the mechanisms regulating cranial suture development remain largely elusive. We have established transgenic mice conditionally expressing an autoactivated platelet-derived growth factor receptor α (PDGFRα) in neural crest cells (NCCs) and their derivatives. In these mice, premature fusion of NCC-derived sutures occurred at early postnatal stages. In vivo and in vitro experiments demonstrated enhanced proliferation of osteoprogenitors and accelerated ossification of osteoblasts. Furthermore, in osteoblasts expressing the autoactivated receptor, we detected an upregulation of the phospholipase C-γ (PLC-γ) pathway. Treatment of differentiating osteoblasts with a PLC-γ-specific inhibitor prevented the mineralization of synthesized bone matrix. Thus, we show for the first time that PDGFRα signaling stimulates osteogenesis of NCC-derived osteoblasts by activating the PLC-γ pathway, suggesting an involvement of this pathway in the etiology of human craniosynostosis.
Induction of beta-platelet-derived growth factor receptor in rat hepatic lipocytes during cellular activation in vivo and in culture.
