{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T13:07:38Z","timestamp":1791896858264,"version":"4.3.4"},"reference-count":30,"publisher":"National Academy of Sciences","issue":"34","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2004,8,24]]},"abstract":"<jats:p>\n                    The\n                    <jats:italic>b<\/jats:italic>\n                    and\n                    <jats:italic>c<\/jats:italic>\n                    variants of fibroblast growth factor receptor 2\n                    <jats:italic>(FGFR2)<\/jats:italic>\n                    differ in sequence, binding specificity, and localization.\n                    <jats:italic>Fgfr2b<\/jats:italic>\n                    , expressed in epithelia, is required for limb outgrowth and branching morphogenesis, whereas the mesenchymal\n                    <jats:italic>Fgfr2c<\/jats:italic>\n                    variant is required by the osteocyte lineage for normal skeletogenesis. Gain-of-function mutations in human FGFR2c are associated with craniosynostosis syndromes. To confirm and extend this evidence, we introduced a Cys342Tyr replacement into\n                    <jats:italic>Fgfr2c<\/jats:italic>\n                    to create a gain-of-function mutation equivalent to a mutation in human Crouzon and Pfeiffer syndromes.\n                    <jats:italic>\n                      Fgfr2c\n                      <jats:sup>C342Y\/<\/jats:sup>\n                    <\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    heterozygote mice are viable and fertile with shortened face, protruding eyes, premature fusion of cranial sutures, and enhanced\n                    <jats:italic>Spp1<\/jats:italic>\n                    expression in the calvaria. Homozygous mutants display multiple joint fusions, cleft palate, and trachea and lung defects, and die shortly after birth. They show enhanced\n                    <jats:italic>Cbfa1<\/jats:italic>\n                    \/\n                    <jats:italic>Runx2<\/jats:italic>\n                    expression without significant change in chondrocyte-specific\n                    <jats:italic>Ihh, PTHrP, Sox9, Col2a<\/jats:italic>\n                    , or\n                    <jats:italic>Col10a<\/jats:italic>\n                    gene expression. Histomorphometric analysis and bone marrow stromal cell culture showed a significant increase of osteoblast progenitors with no change in osteoclastogenic cells. Chondrocyte proliferation was decreased in the skull base at embryonic day 14.5 but not later. These results suggest that long-term aspects of the mutant phenotype, including craniosynostosis, are related to the\n                    <jats:italic>Fgfr2c<\/jats:italic>\n                    regulation of the osteoblast lineage. The effect on early chondrocyte proliferation but not gene expression suggests cooperation of\n                    <jats:italic>Fgfr2c<\/jats:italic>\n                    with\n                    <jats:italic>Fgfr3<\/jats:italic>\n                    in the formation of the cartilage model for endochondral bone.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0405031101","type":"journal-article","created":{"date-parts":[[2004,8,17]],"date-time":"2004-08-17T20:58:12Z","timestamp":1092776292000},"page":"12555-12560","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":203,"title":["A gain-of-function mutation of\n                    <i>Fgfr2c<\/i>\n                    demonstrates the roles of this receptor variant in osteogenesis"],"prefix":"10.1073","volume":"101","author":[{"given":"Veraragavan P.","family":"Eswarakumar","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel; Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06520; and Department of Human Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark C.","family":"Horowitz","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel; Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06520; and Department of Human Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Locklin","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel; Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06520; and Department of Human Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gillian M.","family":"Morriss-Kay","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel; Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06520; and Department of Human Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Lonai","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel; Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06520; and Department of Human Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2004,8,17]]},"reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.25.15292"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1993.1205"},{"key":"e_1_3_2_3_2","first-page":"483","volume":"127","year":"2000","unstructured":"De Moerlooze, L., Spencer-Dene, B., Revest, J., Hajihosseini, M., Rosewell, I. & Dickson, C. 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