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

Susan Marie Perrine, Meng Wu, Nicholas B. Stephens, Divya Kriti, Harm Van Bakel, Ethylin Wang Jabs, Joan Therese Richtsmeier

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article numberdmm.038513
JournalDMM Disease Models and Mechanisms
Volume12
Issue number5
DOIs
StatePublished - Jan 1 2019

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Receptor, Fibroblast Growth Factor, Type 2
Craniosynostoses
Osteogenesis
Mandible
Mutation
Acrocephalosyndactylia
Cartilage
Embryonic Structures
Bone
Laser Capture Microdissection
Microdissection
Bone and Bones
Physiologic Calcification
Genes
Osteoclasts
Chondrocytes
Osteoblasts
Embryonic Development
In Situ Hybridization
Parturition

All Science Journal Classification (ASJC) codes

  • Neuroscience (miscellaneous)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Perrine, Susan Marie ; Wu, Meng ; Stephens, Nicholas B. ; Kriti, Divya ; Van Bakel, Harm ; Jabs, Ethylin Wang ; Richtsmeier, Joan Therese. / Mandibular dysmorphology due to abnormal embryonic osteogenesis in FGFR2-related craniosynostosis mice. In: DMM Disease Models and Mechanisms. 2019 ; Vol. 12, No. 5.
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Mandibular dysmorphology due to abnormal embryonic osteogenesis in FGFR2-related craniosynostosis mice. / Perrine, Susan Marie; Wu, Meng; Stephens, Nicholas B.; Kriti, Divya; Van Bakel, Harm; Jabs, Ethylin Wang; Richtsmeier, Joan Therese.

In: DMM Disease Models and Mechanisms, Vol. 12, No. 5, dmm.038513, 01.01.2019.

Research output: Contribution to journalArticle

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T1 - Mandibular dysmorphology due to abnormal embryonic osteogenesis in FGFR2-related craniosynostosis mice

AU - Perrine, Susan Marie

AU - Wu, Meng

AU - Stephens, Nicholas B.

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AU - Van Bakel, Harm

AU - Jabs, Ethylin Wang

AU - Richtsmeier, Joan Therese

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