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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

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

Schmidt Linnea L Taiyab Aftab A Melvin Vida Senkus VS Jones Kenneth L KL Williams Trevor T

Disease models & mechanisms 20180615 6

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 abnorma ...[more]

PMID: 29752281

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Project description:Fibroblast growth factor (FGF) signaling has been implicated in the regulation of osteogenesis in both intramembranous and endochondral ossifications. In the developing palate, the anterior bony palate forms by direct differentiation of cranial neural crest (CNC)-derived mesenchymal cells, but the signals that regulate the osteogenic cell fate in the developing palate remain unclear. In the present study, we investigated the potential role of FGF signaling in osteogenic fate determination of the palatal mesenchymal cells. We showed that locally activated FGF8 signaling in the anterior palate using a Shox2Cre knock-in allele and an R26RFgf8 allele leads to a unique palatal defect: a complete loss of the palatine process of the maxilla as well as formation of ectopic cartilaginous tissues in the anterior palate. This aberrant developmental process was accompanied by a significantly elevated level of cell proliferation, which contributes to an abnormally thickened palatal tissue, where the palatine process of the maxilla would normally form, and by a complete inhibition of Osterix expression, which accounts for the lack of bone formation. The coexpression of Runx2 initially with Sox9 and subsequently with Col II in the ectopic cartilaginous tissues indicates a conversion of osteogenic fate to a chondrogenic one. Consistent with the unique palatal phenotype, RNA-Sequencing analysis revealed that the augmented FGF8 signaling downregulated genes involved in ossification, biomineral tissue development, and bone mineralization but upregulated genes involved in cell proliferation, cartilage development, and cell fate commitment, which was further supported by quantitative real-time reverse transcription polymerase chain reaction validation of selected genes. Our results demonstrate that FGF8 signaling functions as a negative regulator of osteogenic fate and is sufficient to convert a subset of CNC cell-derived mesenchymal cells into cartilage in the anterior hard palate, which will have implications in future directed differentiation of CNC-derived precursor cells for clinical application.

Dataset Information

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

Publications

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

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