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Molecular and Cellular Biology, February 2009, p. 881-891, Vol. 29, No. 3
0270-7306/09/$08.00+0     doi:10.1128/MCB.00885-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Sustained Platelet-Derived Growth Factor Receptor {alpha} Signaling in Osteoblasts Results in Craniosynostosis by Overactivating the Phospholipase C-{gamma} Pathway{triangledown} ,{dagger}

Anne Moenning,1 Richard Jäger,1 Angela Egert,1 Wolfram Kress,3 Eva Wardelmann,2 and Hubert Schorle1*

Department of Developmental Pathology, Institute of Pathology, University of Bonn, Bonn, Germany,1 Institute of Pathology, University of Bonn, Bonn, Germany,2 Institut für Humangenetik, Biozentrum, Würzburg, Germany3

Received 4 June 2008/ Returned for modification 14 July 2008/ Accepted 20 November 2008

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} (PDGFR{alpha}) 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 PDGFR{alpha} 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.

* Corresponding author. Mailing address: Institute of Pathology, Department of Developmental Pathology, University of Bonn Medical School, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany. Phone: 49-228-28716342. Fax: 49-228-28719757. E-mail: hubert.schorle{at}ukb.uni-bonn.de

{triangledown} Published ahead of print on 1 December 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, February 2009, p. 881-891, Vol. 29, No. 3
0270-7306/09/$08.00+0     doi:10.1128/MCB.00885-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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