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First published online March 24, 2005
doi: 10.1242/10.1242/dev.01786
1 Center for Oral Biology, Department of Biomedical Genetics, Abs Institute of
Biomedical Sciences, School of Medicine and Dentistry, University of
Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA
2 Max Delbruck Center for Molecular Medicine, Robert-Rossle-Strasse 10, 13122
Berlin, Germany
3 Department of Orthopedics, School of Medicine and Dentistry, University of
Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA
4 Department of Genetics and Development, College of Physicians and Surgeons,
Columbia University, 701 West 168th Street, New York, NY 10032, USA
* Author for correspondence (e-mail: wei_hsu{at}urmc.rochester.edu)
Accepted 14 February 2005
Axin1 and its homolog Axin2/conductin/Axil are negative regulators of the canonical Wnt pathway that suppress signal transduction by promoting degradation of ß-catenin. Mice with deletion of Axin1 exhibit defects in axis determination and brain patterning during early embryonic development. We show that Axin2 is expressed in the osteogenic fronts and periosteum of developing sutures during skull morphogenesis. Targeted disruption of Axin2 in mice induces malformations of skull structures, a phenotype resembling craniosynostosis in humans. In the mutants, premature fusion of cranial sutures occurs at early postnatal stages. To elucidate the mechanism of craniosynostosis, we studied intramembranous ossification in Axin2-null mice. The calvarial osteoblast development is significantly affected by the Axin2 mutation. The Axin2 mutant displays enhanced expansion of osteoprogenitors, accelerated ossification, stimulated expression of osteogenic markers and increases in mineralization. Inactivation of Axin2 promotes osteoblast proliferation and differentiation in vivo and in vitro. Furthermore, as the mammalian skull is formed from cranial skeletogenic mesenchyme, which is derived from mesoderm and neural crest, our data argue for a region-specific effect of Axin2 on neural crest dependent skeletogenesis. The craniofacial anomalies caused by the Axin2 mutation are mediated through activation of ß-catenin signaling, suggesting a novel role for the Wnt pathway in skull morphogenesis.
Key words: Axin, Axin2, Wnt, Neural crest, Craniosynostosis
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