{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T03:12:42Z","timestamp":1790651562157,"version":"4.1.0"},"reference-count":49,"publisher":"The Company of Biologists","issue":"17","license":[{"start":{"date-parts":[[1997,9,1]],"date-time":"1997-09-01T00:00:00Z","timestamp":873072000000},"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":[[1997,9,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>Mutations in the human fibroblast growth factor receptor type 2 (FGFR2) gene cause craniosynostosis, particularly affecting the coronal suture. We show here that, in the fetal mouse skull vault, Fgfr2 transcripts are most abundant at the periphery of the membrane bones; they are mutually exclusive with those of osteopontin (an early marker of osteogenic differentiation) but coincide with sites of rapid cell proliferation. Fibroblast growth factor type 2 (FGF2) protein, which has a high affinity for the FGFR2 splice variant associated with craniosynostosis, is locally abundant; immunohistochemical detection showed it to be present at low levels in Fgfr2 expression domains and at high levels in differentiated areas. Implantation of FGF2-soaked beads onto the fetal coronal suture by ex utero surgery resulted in ectopic osteopontin expression, encircled by Fgfr2 expression, after 48 hours. We suggest that increased FGF\/FGFR signalling in the developing skull, whether due to FGFR2 mutation or to ectopic FGF2, shifts the cell proliferation\/differentiation balance towards differentiation by enhancing the normal paracrine down-regulation of Fgfr2.<\/jats:p>","DOI":"10.1242\/dev.124.17.3375","type":"journal-article","created":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T02:56:05Z","timestamp":1619405765000},"page":"3375-3384","source":"Crossref","is-referenced-by-count":179,"title":["<i>Fgfr2<\/i> and <i>osteopontin<\/i> domains in the developing skull vault are mutually exclusive and can be altered by locally applied FGF2"],"prefix":"10.1242","volume":"124","author":[{"given":"S.","family":"Iseki","sequence":"first","affiliation":[{"name":"1 Department of Human Anatomy, South Parks Road, Oxford OX1 3QX, UK"},{"name":"2 Department of Developmental Biology, Graduate School of Dentistry, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. O. M.","family":"Wilkie","sequence":"additional","affiliation":[{"name":"3 Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. K.","family":"Heath","sequence":"additional","affiliation":[{"name":"4 School of Biochemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Ishimaru","sequence":"additional","affiliation":[{"name":"1 Department of Human Anatomy, South Parks Road, Oxford OX1 3QX, UK"},{"name":"2 Department of Developmental Biology, Graduate School of Dentistry, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Eto","sequence":"additional","affiliation":[{"name":"2 Department of Developmental Biology, Graduate School of Dentistry, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. M.","family":"Morriss-Kay","sequence":"additional","affiliation":[{"name":"1 Department of Human Anatomy, South Parks Road, Oxford OX1 3QX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[1997,9,1]]},"reference":[{"key":"2025021404375492500_DEVELOP_124_17_3375C1","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1002\/cne.903550207","article-title":"Model of forebrain regionalisation based on spatio-temporal patterns of POU-III homeobox gene expression, birthdates, and morphological features","volume":"355","author":"Alvarez-Bolado","year":"1995","journal-title":"J. Comp. Neurol"},{"key":"2025021404375492500_DEVELOP_124_17_3375C2","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 Genetics"},{"key":"2025021404375492500_DEVELOP_124_17_3375C3","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1097\/00001665-199505000-00012","article-title":"Crouzon\u2019s disease correlates with low fibroblastic growth factor receptor activity in stenosed cranial sutures","volume":"6","author":"Bresnick","year":"1995","journal-title":"J. Craniofac. Surg"},{"key":"2025021404375492500_DEVELOP_124_17_3375C4","doi-asserted-by":"publisher","first-page":"575","DOI":"10.3171\/jns.1995.83.4.0575","article-title":"Cronic tonsillar herniation in Crouzon\u2019s and Apert\u2019s syndromes: the role of premature synostosis of the lambdoid suture","volume":"83","author":"Cinalli","year":"1995","journal-title":"J. Neurosurg"},{"key":"2025021404375492500_DEVELOP_124_17_3375C5","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1038\/ng0496-390","article-title":"Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3","volume":"12","author":"Colvin","year":"1996","journal-title":"Nat. Genet"},{"key":"2025021404375492500_DEVELOP_124_17_3375C6","doi-asserted-by":"publisher","first-page":"3045","DOI":"10.1101\/gad.8.24.3045","article-title":"Murine FGFR-1 is required for early postimplantation growth and axial organization","volume":"8","author":"Deng","year":"1994","journal-title":"Genes Dev"},{"key":"2025021404375492500_DEVELOP_124_17_3375C7","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1016\/S0092-8674(00)81069-7","article-title":"Fibroblast growth factor receptor 3 is a negative regulator of bone growth","volume":"84","author":"Deng","year":"1996","journal-title":"Cell"},{"key":"2025021404375492500_DEVELOP_124_17_3375C8","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1038\/ng0197-42","article-title":"Mutations of the TWIST gene in the Saethre-Chotzen syndrome","volume":"15","author":"El Ghouzzi","year":"1997","journal-title":"Nature Genet"},{"key":"2025021404375492500_DEVELOP_124_17_3375C9","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1002\/jcp.1041510202","article-title":"Age-related changes in hyaluronan, proteoglycan, collagen and osteonectin synthesis by human bone cells","volume":"151","author":"Fedarko","year":"1992","journal-title":"J. Cell Physiol"},{"key":"2025021404375492500_DEVELOP_124_17_3375C10","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1002\/jcp.1041400110","article-title":"Role of extracellular matrix in the action of basic fibroblast growth factor: matrix as a source of growth factor for long-term stimulation of plasminogen activator and DNA synthesis","volume":"140","author":"Flaumenhaft","year":"1989","journal-title":"J. Cell Physiol"},{"key":"2025021404375492500_DEVELOP_124_17_3375C11","doi-asserted-by":"publisher","first-page":"1651","DOI":"10.1083\/jcb.111.4.1651","article-title":"Heparin and heparan sulphate increase the radius of diffusion and action of basic fibroblast growth factor","volume":"111","author":"Flaumenhaft","year":"1990","journal-title":"J. Cell Biol"},{"key":"2025021404375492500_DEVELOP_124_17_3375C12","first-page":"393","article-title":"A heparin-binding angiogenic protein \u2013 basic fibroblast growth factor \u2013 is stored within basement membrane","volume":"130","author":"Folkman","year":"1988","journal-title":"Am. J. Pathol"},{"key":"2025021404375492500_DEVELOP_124_17_3375C13","doi-asserted-by":"publisher","first-page":"7894","DOI":"10.1073\/pnas.93.15.7894","article-title":"Constitutive receptor activation by Crouzon syndrome mutations in fibroblast growth factor receptor (FGFR)2 and FGFR2\/Neu chimaeras","volume":"93","author":"Galvin","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025021404375492500_DEVELOP_124_17_3375C14","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1038\/ng0197-36","article-title":"Mutations in TWIST, a basic helix-loop-helix transcription factor, in Saethre-Chotzen syndrome","volume":"15","author":"Howard","year":"1997","journal-title":"Nature Genet"},{"key":"2025021404375492500_DEVELOP_124_17_3375C15","first-page":"1","article-title":"Structural and functional diversity in the FGF receptor multigene family","volume":"60","author":"Johnson","year":"1993","journal-title":"Adv. Cancer. Res"},{"key":"2025021404375492500_DEVELOP_124_17_3375C16","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1016\/0092-8674(94)90520-7","article-title":"The ins and outs of fibroblast growth factors","volume":"78","author":"Mason","year":"1994","journal-title":"Cell"},{"key":"2025021404375492500_DEVELOP_124_17_3375C17","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1073\/pnas.89.1.246","article-title":"Determination of ligand-binding specificity by alternative splicing: two distinct growth factor receptors encoded by a single gene","volume":"89","author":"Miki","year":"1992","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025021404375492500_DEVELOP_124_17_3375C18","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1016\/S0140-6736(96)09082-4","article-title":"Prevalence of Pro250Arg mutation of fibroblast growth factor receptor 3 in coronal craniosynostosis","volume":"349","author":"Moloney","year":"1997","journal-title":"Lancet"},{"key":"2025021404375492500_DEVELOP_124_17_3375C19","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1002\/jcp.1041600319","article-title":"Autocrine downregulation of fibroblast growth factor receptors in F9 teratocarcinoma cells","volume":"160","author":"Moscatelli","year":"1994","journal-title":"J. Cell Physiol"},{"key":"2025021404375492500_DEVELOP_124_17_3375C20","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1038\/ng1194-269","article-title":"A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome","volume":"8","author":"Muenke","year":"1994","journal-title":"Nature Genet"},{"key":"2025021404375492500_DEVELOP_124_17_3375C21","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1016\/S0168-9525(00)89088-5","article-title":"Fibroblast-growth-factor receptor mutations in human skeletal disorders","volume":"11","author":"Muenke","year":"1995","journal-title":"Trends Genet"},{"key":"2025021404375492500_DEVELOP_124_17_3375C22","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1093\/oso\/9780199630882.003.0003","article-title":"Exo utero surgery","volume-title":"In Postimplantation Mammalian Embryos: A practical Approach","author":"Muneoka","year":"1990"},{"key":"2025021404375492500_DEVELOP_124_17_3375C23","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1038\/ng0696-233","article-title":"Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia","volume":"13","author":"Naski","year":"1996","journal-title":"Nature Genet"},{"key":"2025021404375492500_DEVELOP_124_17_3375C24","doi-asserted-by":"publisher","first-page":"26037","DOI":"10.1074\/jbc.270.44.26037","article-title":"Constitutive activation of fibroblast growth factor receptor-2 by a point mutation associated with Crouzon syndrome","volume":"270","author":"Neilson","year":"1995","journal-title":"J. Biol. Chem"},{"key":"2025021404375492500_DEVELOP_124_17_3375C25","doi-asserted-by":"publisher","first-page":"25049","DOI":"10.1074\/jbc.271.40.25049","article-title":"Ligand-independent activation of fibroblast growth factor receptors by point mutations in the extracellular, transmembrane and kinase domains","volume":"271","author":"Neilson","year":"1996","journal-title":"J. Biol. Chem"},{"key":"2025021404375492500_DEVELOP_124_17_3375C26","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1083\/jcb.106.2.441","article-title":"Developmental expression of 2ar (osteopontin) and SPARC (osteonectin) RNA as revealed by in situ hybridization","volume":"106","author":"Nomura","year":"1988","journal-title":"J. Cell Biol"},{"key":"2025021404375492500_DEVELOP_124_17_3375C27","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1002\/aja.1001980408","article-title":"Tissue interactions with underlying dura mater inhibit osseous obliteration of developing cranial sutures","volume":"198","author":"Opperman","year":"1993","journal-title":"Dev. Dynam"},{"key":"2025021404375492500_DEVELOP_124_17_3375C28","doi-asserted-by":"publisher","first-page":"15292","DOI":"10.1074\/jbc.271.25.15292","article-title":"Receptor specificity of the fibroblast growth factor family","volume":"271","author":"Ornitz","year":"1996","journal-title":"J. Biol. Chem"},{"key":"2025021404375492500_DEVELOP_124_17_3375C29","doi-asserted-by":"publisher","first-page":"1419","DOI":"10.1242\/dev.113.4.1419","article-title":"Developmental expression of two murine fibroblast growth factor receptors, flg and bek","volume":"113","author":"Orr-Urtreger","year":"1991","journal-title":"Development"},{"key":"2025021404375492500_DEVELOP_124_17_3375C30","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1006\/dbio.1993.1205","article-title":"Developmental localization of the splicing alternatives of fibroblast growth factor receptor-2 (FGFR2)","volume":"158","author":"Orr-Urtreger","year":"1993","journal-title":"Dev. Biol"},{"key":"2025021404375492500_DEVELOP_124_17_3375C31","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1242\/dev.114.1.233","article-title":"Two FGF receptor genes are differentially expressed in epithelial and mesenchymal tissues during limb formation and organogenesis in the mouse","volume":"114","author":"Peters","year":"1992","journal-title":"Development"},{"key":"2025021404375492500_DEVELOP_124_17_3375C32","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1038\/ng0896-492","article-title":"Fibroblast growth factor receptor 2 mutations in Beare-Stevenson cutis gyrata syndrome","volume":"13","author":"Pryzlepa","year":"1996","journal-title":"Nature Genet"},{"key":"2025021404375492500_DEVELOP_124_17_3375C33","first-page":"753","article-title":"PCR-based identification of new receptors: molecular cloning of a receptor for fibroblast growth factors","volume":"6","author":"Raz","year":"1991","journal-title":"Oncogene"},{"key":"2025021404375492500_DEVELOP_124_17_3375C34","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1038\/371252a0","article-title":"Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia","volume":"371","author":"Rousseau","year":"1994","journal-title":"Nature"},{"key":"2025021404375492500_DEVELOP_124_17_3375C35","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1016\/0092-8674(94)90302-6","article-title":"Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism","volume":"78","author":"Shiang","year":"1994","journal-title":"Cell"},{"key":"2025021404375492500_DEVELOP_124_17_3375C36","doi-asserted-by":"publisher","first-page":"3923","DOI":"10.1242\/dev.121.12.3923","article-title":"Longitudinal organization of the anterior neural plate and neural tube","volume":"121","author":"Shimamura","year":"1995","journal-title":"Development"},{"key":"2025021404375492500_DEVELOP_124_17_3375C37","doi-asserted-by":"publisher","first-page":"9850","DOI":"10.1073\/pnas.93.18.9850","article-title":"Fibroblast growth factor (FGF) homologous factors: new members of the FGF family implicated in nervous system development","volume":"93","author":"Smallwood","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025021404375492500_DEVELOP_124_17_3375C38","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1038\/386288a0","article-title":"Activation of Stat1 by mutant fibroblast growth factor receptor activity in thanatophoric dysplasia type II dwarfism","volume":"386","author":"Su","year":"1997","journal-title":"Nature"},{"key":"2025021404375492500_DEVELOP_124_17_3375C39","doi-asserted-by":"publisher","first-page":"2175","DOI":"10.1093\/hmg\/4.11.2175","article-title":"Another mutation that results in the substitution of an unpaired cysteine residue in the extracellular domain of FGFR3 in thanatophoric dysplasia type 1","volume":"4","author":"Tavormina","year":"1995","journal-title":"Hum. Mol. Genet"},{"key":"2025021404375492500_DEVELOP_124_17_3375C40","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1002\/j.1460-2075.1996.tb00384.x","article-title":"Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia","volume":"15","author":"Webster","year":"1996","journal-title":"EMBO J"},{"key":"2025021404375492500_DEVELOP_124_17_3375C41","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/S0168-9525(97)01131-1","article-title":"FGFR activation in skeletal disorders: too much of a good thing","volume":"13","author":"Webster","year":"1997","journal-title":"Trends Genet"},{"key":"2025021404375492500_DEVELOP_124_17_3375C42","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1016\/S0960-9822(95)00102-3","article-title":"Functions of fibroblast growth factors and their receptors","volume":"5","author":"Wilkie","year":"1995","journal-title":"Curr. Biol"},{"key":"2025021404375492500_DEVELOP_124_17_3375C43","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1097\/00019052-199604000-00016","article-title":"Craniosynostosis: novel insights into pathogenesis and treatment","volume":"9","author":"Wilkie","year":"1996","journal-title":"Curr. Opin. Neurobiol"},{"key":"2025021404375492500_DEVELOP_124_17_3375C44","first-page":"75","article-title":"Whole mount in situ hybridization of vertebrate embryos","volume-title":"In In Situ Hybridization: A Practical Approach","author":"Wilkinson","year":"1992"},{"key":"2025021404375492500_DEVELOP_124_17_3375C45","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1002\/(SICI)1520-6408(1996)19:1&lt;74::AID-DVG8&gt;3.0.CO;2-Y","article-title":"Effects of all-trans-retinoic acid on skeletal pattern, 5\u2019HoxD gene expression, and RAR 2\/ 4 promoter activity in embryonic mouse limbs","volume":"18","author":"Wood","year":"1996","journal-title":"Dev. Genet"},{"key":"2025021404375492500_DEVELOP_124_17_3375C46","doi-asserted-by":"publisher","first-page":"3032","DOI":"10.1101\/gad.8.24.3032","article-title":"fgfr-1 is required for embryonic growth and mesodermal patterning during mouse gastrulation","volume":"8","author":"Yamaguchi","year":"1994","journal-title":"Genes. Dev"},{"key":"2025021404375492500_DEVELOP_124_17_3375C47","doi-asserted-by":"publisher","first-page":"15918","DOI":"10.1074\/jbc.271.27.15918","article-title":"Structure and expression of the rat mRNA encoding a novel member of the fibroblast growth factor family","volume":"271","author":"Yamasaki","year":"1996","journal-title":"J. Biol. Chem"},{"key":"2025021404375492500_DEVELOP_124_17_3375C48","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1016\/0092-8674(91)90512-W","article-title":"Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor","volume":"64","author":"Yayon","year":"1991","journal-title":"Cell"},{"key":"2025021404375492500_DEVELOP_124_17_3375C49","doi-asserted-by":"publisher","first-page":"1885","DOI":"10.1002\/j.1460-2075.1992.tb05240.x","article-title":"A confined variable region confers ligand binding specificity on fibroblast growth factor receptors: Implications for the origin of the immunoglobin fold","volume":"11","author":"Yayon","year":"1992","journal-title":"EMBO J"}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.biologists.com\/dev\/article-pdf\/124\/17\/3375\/3126636\/develop_124_17_3375.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/dev\/article-pdf\/124\/17\/3375\/3126636\/develop_124_17_3375.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T04:38:18Z","timestamp":1739507898000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/124\/17\/3375\/39437\/Fgfr2-and-osteopontin-domains-in-the-developing"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1997,9,1]]},"references-count":49,"journal-issue":{"issue":"17","published-print":{"date-parts":[[1997,9,1]]}},"URL":"https:\/\/doi.org\/10.1242\/dev.124.17.3375","relation":{},"ISSN":["0950-1991","1477-9129"],"issn-type":[{"value":"0950-1991","type":"print"},{"value":"1477-9129","type":"electronic"}],"subject":[],"published":{"date-parts":[[1997,9,1]]}}}