Increased FGF8 signaling promotes chondrogenic rather than osteogenic development in the embryonic skull
| Autor: | Vida Senkus Melvin, Aftab Taiyab, Trevor Williams, Kenneth L. Jones, Linnea Schmidt |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Fibroblast Growth Factor 8 Gene Dosage Neuroscience (miscellaneous) lcsh:Medicine Medicine (miscellaneous) Biology Bone and Bones General Biochemistry Genetics and Molecular Biology Fgf8 Craniosynostosis Craniosynostoses Mice 03 medical and health sciences Axin Protein Immunology and Microbiology (miscellaneous) Osteogenesis Cranial vault lcsh:Pathology medicine Animals RNA Messenger Wnt Signaling Pathway Endochondral ossification Alleles Ossification lcsh:R Skull Gene Expression Regulation Developmental Cell Differentiation Chondrogenesis medicine.disease Cell biology Cartilage Phenotype 030104 developmental biology medicine.anatomical_structure Mutation Intramembranous ossification Coronal suture medicine.symptom lcsh:RB1-214 Signal Transduction Research Article |
| Zdroj: | Disease Models & Mechanisms Disease Models & Mechanisms, Vol 11, Iss 6 (2018) |
| ISSN: | 1754-8411 1754-8403 |
| DOI: | 10.1242/dmm.031526 |
| Popis: | 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. Summary: Cranial ossification responds to Fgf8 overexpression in a dose-dependent manner with moderate levels leading to craniosynostosis and higher levels shifting cranial vault ossification to abnormal cartilage formation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|