Early onset of craniosynostosis in an Apert mouse model reveals critical features of this pathology
Open accessAbstract
Activating mutations of FGFRs1-3 cause craniosynostosis (CS), the premature fusion of cranial bones, in man and mouse. The mechanisms by which such mutations lead to CS have been variously ascribed to increased osteoblast proliferation, differentiation, and apoptosis, but it is not always clear how these disturbances relate to the process of suture fusion. We have reassessed coronal suture fusion in an Apert Fgfr2 (S252W) mouse model. We find that the critical event of CS is the early loss of basal sutural mesenchyme as the osteogenic fronts, expressing activated Fgfr2, unite to form a contiguous skeletogenic membrane. A mild increase in osteoprogenitor proliferation precedes but does not accompany this event, and apoptosis is insignificant. On the other hand, the more apical coronal suture initially forms appropriately but then undergoes fusion, albeit at a slower rate, accompanied by a significant decrease in osteoprogenitor proliferation, and increased osteoblast maturation. Apoptosis now accompanies fusion, but is restricted to bone fronts in contact with one another. We correlated these in vivo observations with the intrinsic effects of the activated Fgfr2 S252W mutation in primary osteoblasts in culture, which show an increased capacity for both proliferation and differentiation. Our studies suggest that the major determinant of Fgfr2-induced craniosynostosis is the failure to respond to signals that would halt the recruitment or the advancement of osteoprogenitor cells at the sites where sutures should normally form.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cellular consequences of FGFR2/FGFR3 mutation include enhanced proliferation, differentiation, and apoptosis of osteoblasts bordering the cranial suture mesenchyme; premature differentiation is probably the most important factor leading to craniosynostosis.
“The cellular consequences of mutation are complex, including enhancement of proliferation, differentiation and apoptosis of osteoblasts bordering the cranial suture mesenchyme; premature differentiation is probably the most important factor leading to craniosynostosis.11,12”
From Craniosynostosis (2011) · cites this paper as [12]
Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredMutations in FGFR2 and FGFR3 tend to be highly localised, recurrent missense substitutions that encode gain-of-function proteins.
“Mutations in FGFR2 and FGFR3 tend to encode highly localised, recurrent missense substitutions encoding proteins with gain-of-function properties.”
From Craniosynostosis (2011) · cites this paper as [12]
The Introduction (page unavailable) describes activating mutations in FGFR1–3, supporting the gain-of-function aspect for FGFR2 and FGFR3. The Results section on Fgfr expression (page unavailable) also describes the activating effect of the FGFR2 S252W substitution. Neither passage establishes that mutations in both genes tend to be highly localised, recurrent missense substitutions. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
In situ hybridization; a practical approach
(1993) · International Journal of Biochemistry · doi:10.1016/0020-711x(93)90093-t · Cited by 1,240 · see citing works
Oldberg, Å., Franzén, A., & Heinegård, D. K. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.23.8819 · Cited by 1,088 · see citing works
Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome
Wilkie, A., Slaney, S., Oldridge, M., Poole, M., Ashworth, G., Hockley, A., Hayward, R., David, D., Pulleyn, L., Rutland, P., et al. (1995) · Nature Genetics · doi:10.1038/ng0295-165 · Cited by 933 · see citing works
Ornitz, D. M., & Marie, P. J. (2002) · Genes & Development · doi:10.1101/gad.990702 · Cited by 902 · see citing works
Tissue origins and interactions in the mammalian skull vault.
Jiang, X., Iseki, S., Maxson, R. E., Sucov, H. M., & Morriss-Kay, G. M. (2002) · Developmental Biology · doi:10.1006/dbio.2001.0487 · Cited by 782 · see citing works
A Twist Code Determines the Onset of Osteoblast Differentiation
Bialek, P., Kern, B., Yang, X., Schrock, M., Šošić, D., Hong, N. A., Wu, H., Yu, K., Ornitz, D. M., Olson, E. N., et al. (2004) · Developmental Cell · doi:10.1016/s1534-5807(04)00058-9 · Cited by 674 · see citing works
Yu, K., Xu, J.-S., Liu, Z.-H., Šošić, D., Shao, J.-S., Olson, E., Towler, D., & Ornitz, D. (2003) · Development · doi:10.1242/dev.00491 · Cited by 654 · see citing works
In situ hybridization; a practical approach
(1993) · Comparative Biochemistry and Physiology Part A Physiology · doi:10.1016/0300-9629(93)90060-h · Cited by 652 · see citing works
Mutations in TWIST, a basic helix–loop–helix transcription factor, in Saethre-Chotzen syndrome
Howard, T. D., Paznekas, W. A., Green, E. D., Chiang, L. C., Ma, N. S. F., Luna, R. I. O. D., Delgado, C. G., Gonzalez-Ramos, M., Kline, A. D., & Jabs, E. W. (1997) · Nature Genetics · doi:10.1038/ng0197-36 · Cited by 645 · see citing works
Mutations of the TWIST gene in the Saethre-Chotzene syndrome
Ghouzzi, V. E., Merrer, M. F. L., Perrin‐Schmitt, F., Lajeunie, E., Bénit, P., Rénier, D., Bourgeois, P., Bolcato‐Bellemin, A., Münnich, A., & Bonaventure, J. (1997) · Nature Genetics · doi:10.1038/ng0197-42 · Cited by 639 · see citing works
Evers, R., Kool, M., van Deemter, L., Janssen, H., Calafat, J., Oomen, L. C. J. M., Paulusma, C. C., Elferink, R. P. J. O., Baas, F., Schinkel, A. H., et al. (1998) · Journal of Clinical Investigation · doi:10.1172/jci119886 · Cited by 623 · see citing works
Morriss‐Kay, G. M., & Wilkie, A. O. M. (2005) · Journal of Anatomy · doi:10.1111/j.1469-7580.2005.00475.x · Cited by 483 · see citing works
Integration of FGF and TWIST in calvarial bone and suture development
Rice, D. P. C., Åberg, T., Chan, Y.-S., Tang, Z., Kettunen, P. J., Pakarinen, L., Maxson, R. E., & Thesleff, I. (2000) · Development · doi:10.1242/dev.127.9.1845 · Cited by 407 · see citing works
Cell lineage in mammalian craniofacial mesenchyme.
Yoshida, T., Vivatbutsiri, P., Morriss-Kay, G., Saga, Y., & Iseki, S. (2008) · Mechanisms of Development · doi:10.1016/j.mod.2008.06.007 · Cited by 384 · see citing works
FGF signaling in the developing endochondral skeleton
Ornitz, D. M. (2005) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2005.02.003 · Cited by 355 · see citing works
Iseki, S., Wilkie, A. O. M., & Morriss-Kay, G. M. (1999) · Development · doi:10.1242/dev.126.24.5611 · Cited by 305 · see citing works
The BMP antagonist noggin regulates cranial suture fusion
Warren, S. M., Brunet, L. J., Harland, R. M., Economides, A. N., & Longaker, M. T. (2003) · Nature · doi:10.1038/nature01545 · Cited by 303 · see citing works
Mansukhani, A., Bellosta, P., Sahni, M., & Basilico, C. (2000) · The Journal of Cell Biology · doi:10.1083/jcb.149.6.1297 · Cited by 295 · see citing works
Self-citationLoss of fibroblast growth factor receptor 2 ligand-binding specificity in Apert syndrome.
Yu, K., Herr, A., Waksman, G., & Ornitz, D. (2000) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.97.26.14536 · Cited by 266 · see citing works
TheIIIcalternative ofFgfr2is a positive regulator of bone formation
Eswarakumar, V. P., Ornan, E. M., Pines, M., Antonopoulou, I., Morriss‐Kay, G. M., & Lonai, P. (2002) · Development · doi:10.1242/dev.129.16.3783 · Cited by 259 · see citing works
Akt1 in Osteoblasts and Osteoclasts Controls Bone Remodeling
Kawamura, N., Kugimiya, F., Oshima, Y., Ohba, S., Ikeda, T., Saito, T., Shinoda, Y., Kawasaki, Y., Ogata, N., Hoshi, K., et al. (2007) · PLoS ONE · doi:10.1371/journal.pone.0001058 · Cited by 253 · see citing works
Zhou, Y.-X., Xu, X.-L., Chen, L., Li, C.-L., Brodie, S., & Deng, C.-X. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.13.2001 · Cited by 242 · see citing works
Self-citationHistochemical Localization of Alkaline Phosphatase Activity in Decalcified Bone and Cartilage
Miao, D., & Scutt, A. M. (2002) · Journal of Histochemistry & Cytochemistry · doi:10.1177/002215540205000305 · Cited by 225 · see citing works
Eswarakumar, V. P., Horowitz, M. C., Locklin, R. M., Morriss‐Kay, G. M., & Lonai, P. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0405031101 · Cited by 224 · see citing works
Merrill, A. E., Bochukova, E. G., Brugger, S. M., Ishii, M., Pilz, D. T., Wall, S. A., Lyons, K. M., Wilkie, A. O. M., & Maxson, R. E. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl052 · Cited by 206 · see citing works
Shukla, V., Coumoul, X., Wang, R.-H., Kim, H., & Deng, C. (2007) · Nature Genetics · doi:10.1038/ng2096 · Cited by 203 · see citing works
Self-citationIseki, S., Wilkie, A. O. M., Heath, J. K., Ishimaru, T., Eto, K., & Morriss‐Kay, G. M. (1997) · Development · doi:10.1242/dev.124.17.3375 · Cited by 203 · see citing works
Abnormalities in cartilage and bone development in the Apert syndrome FGFR2+/S252W mouse
Wang, Y., Xiao, R., Yang, F., Karim, B. O., Iacovelli, A. J., Cai, J., Lerner, C. P., Richtsmeier, J. T., Leszl, J. M., Hill, C. A., et al. (2005) · Development · doi:10.1242/dev.01914 · Cited by 200 · see citing works
Activation of p38 Mitogen-Activated Protein Kinase Is Required for Osteoblast Differentiation
Hu, Y., Chan, E., Wang, S. X., et al. (2003) · Endocrinology · doi:10.1210/en.2002-220863 · Cited by 198 · see citing works
Twist1 dimer selection regulates cranial suture patterning and fusion
Connerney, J., Andreeva, V., Leshem, Y., Muentener, C., Mercado, M. A., & Spicer, D. B. (2006) · Developmental Dynamics · doi:10.1002/dvdy.20717 · Cited by 185 · see citing works
Hajihosseini, M., Wilson, S. W., de Moerlooze, L., & Dickson, C. (2001) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.071586898 · Cited by 179 · see citing works
Chen, L., Li, D., Li, C., Engel, A., & Deng, C. (2003) · Bone · doi:10.1016/s8756-3282(03)00222-9 · Cited by 179 · see citing works
Self-citationRegulation of human cranial osteoblast phenotype by FGF-2, FGFR-2 and BMP-2 signaling.
Marie, P. J., Debiais, F., & Haÿ, E. (2002) · PubMed · doi:10.14670/hh-17.877 · Cited by 146 · see citing works
Raucci, A., Bellosta, P., Grassi, R., Basilico, C., & Mansukhani, A. (2007) · Journal of Cellular Physiology · doi:10.1002/jcp.21323 · Cited by 143 · see citing works
Self-citationTwist1 homodimers enhance FGF responsiveness of the cranial sutures and promote suture closure
Connerney, J., Andreeva, V., Leshem, Y., Mercado, M. A., Dowell, K. G., Yang, X., Lindner, V., Friesel, R. E., & Spicer, D. B. (2008) · Developmental Biology · doi:10.1016/j.ydbio.2008.03.037 · Cited by 131 · see citing works
Johnson, D., Iseki, S., Wilkie, A. O. M., & Morriss‐Kay, G. M. (2000) · Mechanisms of Development · doi:10.1016/s0925-4773(99)00278-6 · Cited by 121 · see citing works
Apoptosis in murine calvarial bone and suture development
Rice, D. P. C., Kim, H., & Thesleff, I. (1999) · European Journal Of Oral Sciences · doi:10.1046/j.0909-8836.1999.eos107406.x · Cited by 100 · see citing works
Individual osteoblasts in the developing calvaria express different gene repertoires
Candeliere, G. A., Liu, F., & Aubin, J. E. (2001) · Bone · doi:10.1016/s8756-3282(01)00410-0 · Cited by 94 · see citing works
Suture pathology in craniosynostosis
Albright, A. L., & Byrd, R. P. (1981) · Journal of neurosurgery · doi:10.3171/jns.1981.54.3.0384 · Cited by 90 · see citing works
Craniosynostosis in Twist heterozygous mice: A model for Saethre‐Chotzen syndrome
Carver, E. A., Oram, K. F., & Gridley, T. (2002) · The Anatomical Record · doi:10.1002/ar.10124 · Cited by 88 · see citing works
FGF and FGFR signaling in chondrodysplasias and craniosynostosis
Marie, P. J., Coffin, J. D., & Hurley, M. M. (2005) · Journal of Cellular Biochemistry · doi:10.1002/jcb.20582 · Cited by 86 · see citing works
Robb, L. G., Hartley, L., Begley, C. G., Brodnicki, T. C., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., & Elefanty, A. G. (2000) · Developmental Dynamics · doi:10.1002/1097-0177(2000)9999:9999 · Cited by 78 · see citing works
Lemonnier, J., Delannoy, P., Hott, M., Lomri, A., Modrowski, D., & Marie, P. J. (2000) · Experimental Cell Research · doi:10.1006/excr.2000.4820 · Cited by 77 · see citing works
Tamoxifen induces TGF-β1 activity and apoptosis of human MCF-7 breast cancer cells in vitro
Chen, H., Tritton, T. R., Kenny, N., Absher, M. P., & Chiu, J. (1996) · Journal of Cellular Biochemistry · doi:10.1002/(sici)1097-4644(19960401)61:1 · Cited by 77 · see citing works
Sutural Morphogenesis in the Mouse Calvaria: The Role of Apoptosis
Furtwängler, J. A., Hall, S. H., & Koskinen-Moffett, L. (1985) · Cells Tissues Organs · doi:10.1159/000146099 · Cited by 68 · see citing works
Characteristics of the infant Apert skull and its subsequent development.
Kreiborg, S., & Cohen, M. M. (1990) · PubMed · Cited by 65 · see citing works
Deckelbaum, R. A., Majithia, A. R., Booker, T., Henderson, J. E., & Loomis, C. A. (2005) · Development · doi:10.1242/dev.02171 · Cited by 60 · see citing works
Mathijssen, I. M. J., Vaandrager, J. M., van der Meulen, J. C., et al. (1996) · Plastic & Reconstructive Surgery · doi:10.1097/00006534-199607000-00004 · Cited by 46 · see citing works
Yang, F., Wang, Y., Zhang, Z., et al. (2008) · Bone · doi:10.1016/j.bone.2008.02.008 · Cited by 43 · see citing works
Inhibition of Apoptosis: A Potential Mechanism for Syndromic Craniosynostosis
Dry, G. M., Yasinskaya, Y. I., Williams, J. K., et al. (2001) · Plastic & Reconstructive Surgery · doi:10.1097/00006534-200102000-00019 · Cited by 38 · see citing works
Apoptotic Cell Death During Normal Embryogenesis of the Coronal Suture
Bourez, R. L. J. H., Mathijssen, I. M. J., Vaandrager, J. M., & Vermeij‐Keers, C. (1997) · Journal of Craniofacial Surgery · doi:10.1097/00001665-199711000-00002 · Cited by 21 · see citing works
Ali, J., Mansukhani, A., & Basilico, C. (1995) · Journal of Cellular Physiology · doi:10.1002/jcp.1041650225 · Cited by 15 · see citing works
Self-citationIshikawa, T., Kibe, T., & Wada, Y. (1996) · American Journal of Medical Genetics · doi:10.1002/(sici)1096-8628(19960424)62:4 · Cited by 13 · see citing works
Apoptosis in a Rodent Model of Cranial Suture Fusion: In Situ Imaging and Gene Expression Analysis
Fong, K. D., Song, H. M., Nacamuli, R. P., Franc, B. L., Aparici, C. M., Fang, T. D., Warren, S. M., Contag, C. H., Blankenberg, F. G., & Longaker, M. T. (2004) · Plastic & Reconstructive Surgery · doi:10.1097/01.prs.0000121182.01199.c1 · Cited by 12 · see citing works
Collagenase in Cranial Morphogenesis
Holmbeck, K. (2005) · Cells Tissues Organs · doi:10.1159/000091377 · Cited by 5 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Lomri A Lemonnier J Hott M de Parseval N Lajeunie E Munnich A Renier D Marie PJ 1998 Increased calvaria cell differentiation and bone matrix formation induced by fibroblast growth factor receptor 2 mutations in Apert syndrome J Clin Invest 101 1310 7 9502772 PMC508685
Cited by
Sorted by citations
Johnson, D., & Wilkie, A. O. M. (2011) · European Journal of Human Genetics · doi:10.1038/ejhg.2010.235 · Cited by 499 · see citing works
A Genetic-Pathophysiological Framework for Craniosynostosis
Twigg, S. R. F., & Wilkie, A. O. M. (2015) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2015.07.006 · Cited by 276 · see citing works
- Authors
- Holmes, G., Rothschild, G., Roy, U. B., Deng, C.-X., Mansukhani, A., & Basilico, C.
- Affiliations
- NYU Langone Health (US)
- National Institutes of Health (US)
- Corresponding author
- Basilico, Claudio
- Venue
- Developmental Biology
- Publisher
- Elsevier BV
- Published
- 2009-04
- Volume
- 328
- Issue
- 2
- Pages
- 273-284
- ISSN
- 0012-1606 (ISSN-L)
- PMC
- PMC2674120
- OpenAlex
- W2046072419
- Cited by
- 104
- References
- 55
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 2 · 2023: 5 · 2022: 6 · 2021: 8 · 2020: 5 · 2019: 3 · 2018: 7 · 2017: 3 · 2016: 8 · 2015: 8 · 2014: 4 · 2013: 9 · 2012: 13
- FWCI
- 6.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR 051358, R01AR051358)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Craniofacial Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › dental development and anomalies
- Keywords
- craniosynostosis, Apert syndrome, FGFR signaling, osteogenic differentiation, osteoblast apoptosis, osteoblasts, mouse model
- MeSH terms
- Acrocephalosyndactylia, Animals, Cell Differentiation, Cells, Cultured, Craniosynostoses, Mesoderm, Mice, Mutant Strains, Osteoblasts, Stem Cells, Apoptosis, Cell Proliferation, Mice, Receptor, Fibroblast Growth Factor, Type 2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
