Related Experiment Video
Updated: May 21, 2026
Dissection of the Auditory Bulla in Postnatal Mice: Isolation of the Middle Ear Bones and Histological Analysis
Published on: January 4, 2017
Mesodermal expression of Fgfr2S252W is necessary and sufficient to induce craniosynostosis in a mouse model of Apert
Greg Holmes1, Claudio Basilico
1Department of Microbiology, New York University School of Medicine, 550 1st Ave, New York, NY 10016, USA. gregory.holmes@exchange.mssm.edu
Insights
Craniosynostosis, or premature skull fusion, can result from genetic mutations. In Apert syndrome, a specific FGFR2 mutation causes craniosynostosis by inducing bone formation within the skull suture, not by cell mixing.
Area of Science:
- Developmental biology
- Genetics
- Pediatric disease
Background:
- Craniosynostosis is premature fusion of skull bones, affecting 1 in 2500 births.
- Syndromic craniosynostosis often results from genetic mutations, including FGFRs and TWIST1.
- Previous research in TWIST1 models showed cell mixing during suture fusion, but its role in FGFR-related craniosynostosis was unknown.
Purpose of the Study:
- To investigate the mechanism of suture fusion in the Apert Fgfr2(S252W) mouse model.
- To determine the role of cell lineage and migration in FGFR-mediated craniosynostosis.
Main Methods:
- Utilized Cre/lox recombination to induce specific gene expression in neural crest or mesoderm.
- Generated conditional mouse models for Apert syndrome (Fgfr2(S252W) mutation).
- Analyzed skull development and suture fusion in mutant mice.
Main Results:
- Mutation in the mesoderm alone was sufficient to cause craniosynostosis.
- Mutation in the neural crest did not cause craniosynostosis.
- Suture fusion occurred without disruption of the lineage border or aberrant cell migration; the suture mesenchyme underwent osteogenesis.
- Ruled out roles for dura mater or skull base changes.
Conclusions:
- FGFR2 mutations in Apert syndrome cause craniosynostosis through direct induction of osteogenesis in the suture mesenchyme.
- Cellular lineage mixing is not the mechanism for suture fusion in this FGFR-mediated craniosynostosis model.
- Conditional mutant mice enable further study of Apert syndrome post-natally.
Abstract:
Coordinated growth of the skull and brain are vital to normal human development. Craniosynostosis, the premature fusion of the calvarial bones of the skull, is a relatively common pediatric disease, occurring in 1 in 2500 births, and requires significant surgical management, especially in syndromic cases. Syndromic craniosynostosis is caused by a variety of genetic lesions, most commonly by activating mutations of FGFRs 1-3, and inactivating mutations of TWIST1. In a mouse model of TWIST1 haploinsufficiency, cell mixing between the neural crest-derived frontal bone and mesoderm-derived parietal bone accompanies coronal suture fusion during embryonic development. However, the relevance of lineage mixing in craniosynostosis induced by activating FGFR mutations is unknown. Here, we demonstrate a novel mechanism of suture fusion in the Apert Fgfr2(S252W) mouse model. Using Cre/lox recombination we simultaneously induce expression of Fgfr2(S252W) and β-galactosidase in either the neural crest or mesoderm of the skull. We show that mutation of the mesoderm alone is necessary and sufficient to cause craniosynostosis, while mutation of the neural crest is neither. The lineage border is not disrupted by aberrant cell migration during fusion. Instead, the suture mesenchyme itself remains intact and is induced to undergo osteogenesis. We eliminate postulated roles for dura mater or skull base changes in craniosynostosis. The viability of conditionally mutant mice also allows post-natal assessment of other aspects of Apert syndrome.
