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First published online 23 June 2005
doi: 10.1242/dev.01914

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Abnormalities in cartilage and bone development in the Apert syndrome FGFR2^+/S252W mouse

Yingli Wang^1,4,*, Ran Xiao^1,4,*, Fan Yang⁵, Baktiar O. Karim², Anthony J. Iacovelli^1,4, Juanliang Cai^1,4, Charles P. Lerner⁶, Joan T. Richtsmeier^4,7, Jen M. Leszl⁷, Cheryl A. Hill⁷, Kai Yu⁸, David M. Ornitz⁸, Jennifer Elisseeff⁵, David L. Huso² and Ethylin Wang Jabs^1,3,4,

¹ Institute of Genetic Medicine, Department of Pediatrics, The Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA
² Department of Comparative Medicine, The Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA
³ Department of Medicine and Plastic Surgery, The Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA
⁴ Center for Craniofacial Development and Disorders, The Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA
⁵ Department of Biomedical Engineering, The Johns Hopkins University, 3400 N. Charles Street, Clark 106, Baltimore, MD 21218, USA
⁶ Departments of Cell Biology/Microinjection and Microchemistry, The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
⁷ Department of Anthropology, The Pennsylvania State University, 409 Carpenter Building, University Park, PA 16802, USA
⁸ Department of Molecular Biology and Pharmacology, Washington University Medical School, 660 S. Euclid Avenue, St Louis, MO 63110, USA

Author for correspondence (e-mail: ejabs1{at}jhem.jhmi.edu)

Accepted 13 May 2005

Apert syndrome is an autosomal dominant disorder characterized by malformations of the skull, limbs and viscera. Two-thirds of affected individuals have a S252W mutation in fibroblast growth factor receptor 2 (FGFR2). To study the pathogenesis of this condition, we generated a knock-in mouse model with this mutation. The Fgfr2^+/S252W mutant mice have abnormalities of the skeleton, as well as of other organs including the brain, thymus, lungs, heart and intestines. In the mutant neurocranium, we found a midline sutural defect and craniosynostosis with abnormal osteoblastic proliferation and differentiation. We noted ectopic cartilage at the midline sagittal suture, and cartilage abnormalities in the basicranium, nasal turbinates and trachea. In addition, from the mutant long bones, in vitro cell cultures grown in osteogenic medium revealed chondrocytes, which were absent in the controls. Our results suggest that altered cartilage and bone development play a significant role in the pathogenesis of the Apert syndrome phenotype.

Key words: Apert syndrome, Fibroblast growth factor receptor 2, Mouse, Cartilage, Bone, Mesenchyme, Neural crest, Skull, Suture, Craniosynostosis

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