{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T12:58:03Z","timestamp":1791118683847,"version":"4.1.0"},"reference-count":67,"publisher":"The Company of Biologists","issue":"9","license":[{"start":{"date-parts":[[2000,5,1]],"date-time":"2000-05-01T00:00:00Z","timestamp":957139200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.biologists.com\/user-licence-1-1\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2000,5,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Mutations in the FGFR1-FGFR3 and TWIST genes are known to cause craniosynostosis, the former by constitutive activation and the latter by haploinsufficiency. Although clinically achieving the same end result, the premature fusion of the calvarial bones, it is not known whether these genes lie in the same or independent pathways during calvarial bone development and later in suture closure. We have previously shown that Fgfr2c is expressed at the osteogenic fronts of the developing calvarial bones and that, when FGF is applied via beads to the osteogenic fronts, suture closure is accelerated (Kim, H.-J., Rice, D. P. C., Kettunen, P. J. and Thesleff, I. (1998)Development 125, 1241-1251). In order to investigate further the role of FGF signalling during mouse calvarial bone and suture development, we have performed detailed expression analysis of the splicing variants of Fgfr1-Fgfr3 and Fgfr4, as well as their potential ligand Fgf2. The IIIc splice variants of Fgfr1-Fgfr3 as well as the IIIb variant of Fgfr2 being expressed by differentiating osteoblasts at the osteogenic fronts (E15). In comparison to Fgf9, Fgf2 showed a more restricted expression pattern being primarily expressed in the sutural mesenchyme between the osteogenic fronts. We also carried out a detailed expression analysis of the helix-loop-helix factors (HLH) Twist and Id1 during calvaria and suture development (E10-P6). Twist and Id1 were expressed by early preosteoblasts, in patterns that overlapped those of the FGF ligands, but as these cells differentiated their expression dramatically decreased. Signalling pathways were further studied in vitro, in E15 mouse calvarial explants. Beads soaked in FGF2 induced Twist and inhibited Bsp, a marker of functioning osteoblasts. Meanwhile, BMP2 upregulated Id1. Id1 is a dominant negative HLH thought to inhibit basic HLH such as Twist. In Drosophila, the FGF receptor FR1 is known to be downstream of Twist. We demonstrated that in Twist+\/\u2212 mice, FGFR2 protein expression was altered. We propose a model of osteoblast differentiation integrating Twist and FGF in the same pathway, in which FGF acts both at early and late stages. Disruption of this pathway may lead to craniosynostosis.<\/jats:p>","DOI":"10.1242\/dev.127.9.1845","type":"journal-article","created":{"date-parts":[[2021,4,23]],"date-time":"2021-04-23T16:16:12Z","timestamp":1619194572000},"page":"1845-1855","source":"Crossref","is-referenced-by-count":355,"title":["Integration of FGF and TWIST in calvarial bone and suture development"],"prefix":"10.1242","volume":"127","author":[{"given":"David P. C.","family":"Rice","sequence":"first","affiliation":[{"name":"00014 University of Helsinki 1 Institute of Biotechnology and Institute of Dentistry, PO Box 56 , , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"\u00c5berg","sequence":"additional","affiliation":[{"name":"00014 University of Helsinki 1 Institute of Biotechnology and Institute of Dentistry, PO Box 56 , , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Shun","family":"Chan","sequence":"additional","affiliation":[{"name":"2 USC Medical School, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zequn","family":"Tang","sequence":"additional","affiliation":[{"name":"2 USC Medical School, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e4ivi","family":"J. Kettunen","sequence":"additional","affiliation":[{"name":"00014 University of Helsinki 1 Institute of Biotechnology and Institute of Dentistry, PO Box 56 , , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila","family":"Pakarinen","sequence":"additional","affiliation":[{"name":"00014 University of Helsinki 1 Institute of Biotechnology and Institute of Dentistry, PO Box 56 , , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Robert E.","family":"Maxson","sequence":"additional","affiliation":[{"name":"2 USC Medical School, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irma","family":"Thesleff","sequence":"additional","affiliation":[{"name":"00014 University of Helsinki 1 Institute of Biotechnology and Institute of Dentistry, PO Box 56 , , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2000,5,1]]},"reference":[{"key":"2023051200252630400_DEVELOP_127_9_1845C1","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1242\/dev.113.1.79","article-title":"Cells with persistent twist expression are the embryonic precursors of adult muscles in Drosophila","volume":"113","author":"Bate","year":"1991","journal-title":"Development"},{"key":"2023051200252630400_DEVELOP_127_9_1845C2","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1038\/ng1096-174","article-title":"Identical mutations in three different fibroblast growth factor receptor genes in autosomal dominant craniosynostosis syndromes","volume":"14","author":"Bellus","year":"1996","journal-title":"Nature Genet"},{"key":"2023051200252630400_DEVELOP_127_9_1845C3","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/0092-8674(90)90214-Y","article-title":"The protein Id: a negative regulator of helix-loop-helix DNA binding proteins","volume":"61","author":"Benezra","year":"1990","journal-title":"Cell"},{"key":"2023051200252630400_DEVELOP_127_9_1845C4","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1007\/BF02555854","article-title":"Expression of bone sialoprotein (BSP) in developing human tissues","volume":"49","author":"Bianco","year":"1991","journal-title":"Calcif. 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