Increased FGF8 signaling promotes chondrogenic rather than osteogenic development in the embryonic skull.

ABSTRACT: The bones of the cranial vault are formed directly from mesenchymal cells through intramembranous ossification rather than via a cartilage intermediate. Formation and growth of the skull bones involves the interaction of multiple cell-cell signaling pathways, with fibroblast growth factors (FGFs) and their receptors exerting a prominent influence. Mutations within the FGF signaling pathway are the most frequent cause of craniosynostosis, which is a common human craniofacial developmental abnormality characterized by the premature fusion of the cranial sutures. Here, we have developed new mouse models to investigate how different levels of increased FGF signaling can affect the formation of the calvarial bones and associated sutures. Whereas moderate Fgf8 overexpression resulted in delayed ossification followed by craniosynostosis of the coronal suture, higher Fgf8 levels promoted a loss of ossification and favored cartilage over bone formation across the skull. By contrast, endochondral bones were still able to form and ossify in the presence of increased levels of Fgf8, although the growth and mineralization of these bones were affected to varying extents. Expression analysis demonstrated that abnormal skull chondrogenesis was accompanied by changes in the genes required for Wnt signaling. Moreover, further analysis indicated that the pathology was associated with decreased Wnt signaling, as the reduction in ossification could be partially rescued by halving Axin2 gene dosage. Taken together, these findings indicate that mesenchymal cells of the skull are not fated to form bone, but can be forced into a chondrogenic fate through the manipulation of FGF8 signaling. These results have implications for evolution of the different methods of ossification as well as for therapeutic intervention in craniosynostosis.

SUBMITTER: Schmidt L 

PROVIDER: S-EPMC6031357 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature