The craniofacial anomalies caused by the Axin2 mutation are mediated through activation of β-catenin signaling, suggesting a novel role for the Wnt pathway in skull morphogenesis.Ĭraniofacial morphogenesis is regulated by complex interactions between the surface and neural ectoderms, endoderm, paraxial mesoderm and cranial neural crest ( Francis-West et al.,1998). 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. Inactivation of Axin2 promotes osteoblast proliferation and differentiation in vivo and in vitro. The Axin2mutant displays enhanced expansion of osteoprogenitors, accelerated ossification, stimulated expression of osteogenic markers and increases in mineralization. The calvarial osteoblast development is significantly affected by the Axin2 mutation. To elucidate the mechanism of craniosynostosis, we studied intramembranous ossification in Axin2-null mice. In the mutants, premature fusion of cranial sutures occurs at early postnatal stages. Targeted disruption of Axin2 in mice induces malformations of skull structures, a phenotype resembling craniosynostosis in humans. We show that Axin2 is expressed in the osteogenic fronts and periosteum of developing sutures during skull morphogenesis. Mice with deletion of Axin1 exhibit defects in axis determination and brain patterning during early embryonic development. Axin1 and its homolog Axin2/conductin/Axil are negative regulators of the canonical Wnt pathway that suppress signal transduction by promoting degradation of β-catenin.

Tyrian 2000 mouse problem