Mandibular dysmorphology due to abnormal embryonic osteogenesis in FGFR2-related craniosynostosis mice

Dis Model Mech. 2019 May 30;12(5):dmm038513. doi: 10.1242/dmm.038513.


One diagnostic feature of craniosynostosis syndromes is mandibular dysgenesis. Using three mouse models of Apert, Crouzon and Pfeiffer craniosynostosis syndromes, we investigated how embryonic development of the mandible is affected by fibroblast growth factor receptor 2 (Fgfr2) mutations. Quantitative analysis of skeletal form at birth revealed differences in mandibular morphology between mice carrying Fgfr2 mutations and their littermates that do not carry the mutations. Murine embryos with the mutations associated with Apert syndrome in humans (Fgfr2+/S252W and Fgfr2+/P253R ) showed an increase in the size of the osteogenic anlagen and Meckel's cartilage (MC). Changes in the microarchitecture and mineralization of the developing mandible were visualized using histological staining. The mechanism for mandibular dysgenesis in the Apert Fgfr2+/S252W mouse resulting in the most severe phenotypic effects was further analyzed in detail and found to occur to a lesser degree in the other craniosynostosis mouse models. Laser capture microdissection and RNA-seq analysis revealed transcriptomic changes in mandibular bone at embryonic day 16.5 (E16.5), highlighting increased expression of genes related to osteoclast differentiation and dysregulated genes active in bone mineralization. Increased osteoclastic activity was corroborated by TRAP assay and in situ hybridization of Csf1r and Itgb3 Upregulated expression of Enpp1 and Ank was validated in the mandible of Fgfr2+/S252W embryos, and found to result in elevated inorganic pyrophosphate concentration. Increased proliferation of osteoblasts in the mandible and chondrocytes forming MC was identified in Fgfr2+/S252W embryos at E12.5. These findings provide evidence that FGFR2 gain-of-function mutations differentially affect cartilage formation and intramembranous ossification of dermal bone, contributing to mandibular dysmorphogenesis in craniosynostosis syndromes.This article has an associated First Person interview with the joint first authors of the paper.

Keywords: Apert syndrome; Cartilage; Crouzon syndrome; FGFR2; Osteoclast; Pfeiffer syndrome; Transcriptome.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Proliferation
  • Chondrocytes / pathology
  • Craniosynostoses / embryology*
  • Craniosynostoses / pathology*
  • Diphosphates / metabolism
  • Disease Models, Animal
  • Embryo, Mammalian / abnormalities*
  • Embryo, Mammalian / pathology
  • Mandible / abnormalities*
  • Mandible / embryology*
  • Mandible / pathology
  • Mice
  • Models, Biological
  • Osteoblasts / pathology
  • Osteogenesis*
  • Receptor, Fibroblast Growth Factor, Type 2 / genetics*


  • Diphosphates
  • Receptor, Fibroblast Growth Factor, Type 2