title: Sustained platelet-derived growth factor receptor alpha signaling in osteoblasts results in craniosynostosis by overactivating the phospholipase C-gamma pathway.
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 alpha (PDGFRalpha) 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-gamma (PLC-gamma) pathway. Treatment of differentiating osteoblasts with a PLC-gamma-specific inhibitor prevented the mineralization of synthesized bone matrix. Thus, we show for the first time that PDGFRalpha signaling stimulates osteogenesis of NCC-derived osteoblasts by activating the PLC-gamma pathway, suggesting an involvement of this pathway in the etiology of human craniosynostosis.
authors.affiliation: Department of Developmental Pathology, Institute of Pathology, University of Bonn, Bonn, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Moenning
authors.forename: Richard
authors.initials: R
authors.lastname: Jäger
authors.forename: Angela
authors.initials: A
authors.lastname: Egert
authors.forename: Wolfram
authors.initials: W
authors.lastname: Kress
authors.forename: Eva
authors.initials: E
authors.lastname: Wardelmann
authors.forename: Hubert
authors.initials: H
authors.lastname: Schorle
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation; D003398:Craniosynostoses / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D019426:Integrases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009432:Neural Crest / Q000166:cytology; D010006:Osteoblasts / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism*; D010766:Phosphorylation; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D012886:Skull / Q000002:abnormalities / Q000201:enzymology; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology; D019076:Transgenes
chemical_list: D020796:Receptor, Platelet-Derived Growth Factor alpha; C045073:Cre recombinase; D019426:Integrases; D051966:Phospholipase C gamma