{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:48:01Z","timestamp":1790837281229,"version":"4.1.0"},"reference-count":86,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"am","delay-in-days":1233,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 DE019843"],"award-info":[{"award-number":["R01 DE019843"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011866","name":"Colorado Clinical and Translational Sciences Institute","doi-asserted-by":"publisher","award":["TL1 TR001081"],"award-info":[{"award-number":["TL1 TR001081"]}],"id":[{"id":"10.13039\/100011866","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>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 prominent influence. Mutations within this 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 impact the formation of the calvarial bones and associated sutures. While 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. In contrast, endochondral bones were still able to form and ossify in the presence of increased Fgf8, though the growth and mineralization of these bones were impacted to varying extents. Expression analysis demonstrated that abnormal skull chondrogenesis was accompanied by changes in genes required for Wnt signaling. Moreover, further analysis indicated that the pathology was associated with decreased Wnt signaling since 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 via manipulation of FGF8 signaling. These results have implications for evolution of the different methods of ossification as well as for therapeutic intervention in craniosynostosis.<\/jats:p>","DOI":"10.1242\/dmm.031526","type":"journal-article","created":{"date-parts":[[2018,5,10]],"date-time":"2018-05-10T12:25:11Z","timestamp":1525955111000},"source":"Crossref","is-referenced-by-count":23,"title":["Increased FGF8 signaling promotes chondrogenic rather than osteogenic development in the embryonic skull"],"prefix":"10.1242","author":[{"given":"Linnea","family":"Schmidt","sequence":"first","affiliation":[{"name":"Program of Reproductive Sciences and Integrated Physiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"},{"name":"Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aftab","family":"Taiyab","sequence":"additional","affiliation":[{"name":"Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vida Senkus","family":"Melvin","sequence":"additional","affiliation":[{"name":"Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth L.","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2416-4603","authenticated-orcid":false,"given":"Trevor","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"},{"name":"Department of Cell and Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"},{"name":"Department of Pediatrics, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2018,1,1]]},"reference":[{"key":"2021042612402808400_DMM031526C1","doi-asserted-by":"publisher","first-page":"2813","DOI":"10.1101\/gad.1017802","article-title":"The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6","volume":"16","author":"Akiyama","year":"2002","journal-title":"Genes Dev."},{"key":"2021042612402808400_DMM031526C2","doi-asserted-by":"publisher","first-page":"4759","DOI":"10.1128\/MCB.01849-07","article-title":"Fibroblast growth factor signaling uses multiple mechanisms to inhibit wnt-induced transcription in osteoblasts","volume":"28","author":"Ambrosetti","year":"2008","journal-title":"Mol. 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