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A gain-of-function mutation of Fgfr2c demonstrates the roles of this receptor variant in osteogenesis.
Proc Natl Acad Sci U S A 2004; 101(34):12555-60PN

Abstract

The b and c variants of fibroblast growth factor receptor 2 (FGFR2) differ in sequence, binding specificity, and localization. Fgfr2b, expressed in epithelia, is required for limb outgrowth and branching morphogenesis, whereas the mesenchymal Fgfr2c 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 Fgfr2c to create a gain-of-function mutation equivalent to a mutation in human Crouzon and Pfeiffer syndromes. Fgfr2c(C342Y/)(+) heterozygote mice are viable and fertile with shortened face, protruding eyes, premature fusion of cranial sutures, and enhanced Spp1 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 Cbfa1/Runx2 expression without significant change in chondrocyte-specific Ihh, PTHrP, Sox9, Col2a, or Col10a 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 Fgfr2c regulation of the osteoblast lineage. The effect on early chondrocyte proliferation but not gene expression suggests cooperation of Fgfr2c with Fgfr3 in the formation of the cartilage model for endochondral bone.

Authors+Show Affiliations

Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15316116

Citation

Eswarakumar, Veraragavan P., et al. "A Gain-of-function Mutation of Fgfr2c Demonstrates the Roles of This Receptor Variant in Osteogenesis." Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 34, 2004, pp. 12555-60.
Eswarakumar VP, Horowitz MC, Locklin R, et al. A gain-of-function mutation of Fgfr2c demonstrates the roles of this receptor variant in osteogenesis. Proc Natl Acad Sci USA. 2004;101(34):12555-60.
Eswarakumar, V. P., Horowitz, M. C., Locklin, R., Morriss-Kay, G. M., & Lonai, P. (2004). A gain-of-function mutation of Fgfr2c demonstrates the roles of this receptor variant in osteogenesis. Proceedings of the National Academy of Sciences of the United States of America, 101(34), pp. 12555-60.
Eswarakumar VP, et al. A Gain-of-function Mutation of Fgfr2c Demonstrates the Roles of This Receptor Variant in Osteogenesis. Proc Natl Acad Sci USA. 2004 Aug 24;101(34):12555-60. PubMed PMID: 15316116.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A gain-of-function mutation of Fgfr2c demonstrates the roles of this receptor variant in osteogenesis. AU - Eswarakumar,Veraragavan P, AU - Horowitz,Mark C, AU - Locklin,Rachel, AU - Morriss-Kay,Gillian M, AU - Lonai,Peter, Y1 - 2004/08/17/ PY - 2004/8/19/pubmed PY - 2004/10/19/medline PY - 2004/8/19/entrez SP - 12555 EP - 60 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 101 IS - 34 N2 - The b and c variants of fibroblast growth factor receptor 2 (FGFR2) differ in sequence, binding specificity, and localization. Fgfr2b, expressed in epithelia, is required for limb outgrowth and branching morphogenesis, whereas the mesenchymal Fgfr2c 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 Fgfr2c to create a gain-of-function mutation equivalent to a mutation in human Crouzon and Pfeiffer syndromes. Fgfr2c(C342Y/)(+) heterozygote mice are viable and fertile with shortened face, protruding eyes, premature fusion of cranial sutures, and enhanced Spp1 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 Cbfa1/Runx2 expression without significant change in chondrocyte-specific Ihh, PTHrP, Sox9, Col2a, or Col10a 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 Fgfr2c regulation of the osteoblast lineage. The effect on early chondrocyte proliferation but not gene expression suggests cooperation of Fgfr2c with Fgfr3 in the formation of the cartilage model for endochondral bone. SN - 0027-8424 UR - https://www.unboundmedicine.com/medline/citation/15316116/A_gain_of_function_mutation_of_Fgfr2c_demonstrates_the_roles_of_this_receptor_variant_in_osteogenesis_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=15316116 DB - PRIME DP - Unbound Medicine ER -