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Overexpression of Fgfr2c causes craniofacial bone hypoplasia and ameliorates craniosynostosis in the Crouzon mouse.

ABSTRACT: FGFR2c regulates many aspects of craniofacial and skeletal development. Mutations in the FGFR2 gene are causative of multiple forms of syndromic craniosynostosis, including Crouzon syndrome. Paradoxically, mouse studies have shown that the activation (Fgfr2c C342Y; a mouse model for human Crouzon syndrome), as well as the removal (Fgfr2c null), of the FGFR2c isoform can drive suture abolishment. This study aims to address the downstream effects of pathogenic FGFR2c signalling by studying the effects of Fgfr2c overexpression. Conditional overexpression of Fgfr2c (R26R Fgfr2c;?act) results in craniofacial hypoplasia as well as microtia and cleft palate. Contrary to Fgfr2c null and Fgfr2c C342Y, Fgfr2c overexpression is insufficient to drive onset of craniosynostosis. Examination of the MAPK/ERK pathway in the embryonic sutures of Fgfr2c C342Y and R26R Fgfr2c;?act mice reveals that both mutants have increased pERK expression. The contrasting phenotypes between Fgfr2c C342Y and R26R Fgfr2c;?act mice prompted us to assess the impact of the Fgfr2c overexpression allele on the Crouzon mouse (Fgfr2c C342Y), in particular its effects on the coronal suture. Our results demonstrate that Fgfr2c overexpression is sufficient to partially rescue craniosynostosis through increased proliferation and reduced osteogenic activity in E18.5 Fgfr2c C342Y embryos. This study demonstrates the intricate balance of FGF signalling required for correct calvarial bone and suture morphogenesis, and that increasing the expression of the wild-type FGFR2c isoform could be a way to prevent or delay craniosynostosis progression.

SUBMITTER: Lee KKL

PROVIDER: S-EPMC6262810 | biostudies-other | 2018 Nov

REPOSITORIES: biostudies-other

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Overexpression of Fgfr2c causes craniofacial bone hypoplasia and ameliorates craniosynostosis in the Crouzon mouse.

Lee Kevin K L KKL Peskett Emma E Quinn Charlotte M CM Aiello Rosanna R Adeeva Liliya L Moulding Dale A DA Stanier Philip P Pauws Erwin E

Disease models & mechanisms 20181109 11

FGFR2c regulates many aspects of craniofacial and skeletal development. Mutations in the FGFR2 gene are causative of multiple forms of syndromic craniosynostosis, including Crouzon syndrome. Paradoxically, mouse studies have shown that the activation (Fgfr2cC342Y; a mouse model for human Crouzon syndrome), as well as the removal (Fgfr2cnull), of the FGFR2c isoform can drive suture abolishment. This study aims to address the downstream effects of pathoge ...[more]

PMID: 30266836

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Project description:Tissue-nonspecific alkaline phosphatase (TNAP) is an enzyme present on the surface of mineralizing cells and their derived matrix vesicles that promotes hydroxyapatite crystal growth. Hypophosphatasia (HPP) is an inborn-error-of-metabolism that, dependent upon age of onset, features rickets or osteomalacia due to loss-of function mutations in the gene (Alpl) encoding TNAP. Craniosynostosis is prevalent in infants with HPP and other forms of rachitic disease but how craniosynostosis develops in these disorders is unknown.Because craniosynostosis carries high morbidity, we are investigating craniofacial skeletal abnormalities in Alpl(-/-) mice to establish these mice as a model of HPP-associated craniosynostosis and determine mechanisms by which TNAP influences craniofacial skeletal development.Cranial bone, cranial suture and cranial base abnormalities were analyzed by micro-CT and histology. Craniofacial shape abnormalities were quantified using digital calipers. TNAP expression was suppressed in MC3T3E1(C4) calvarial cells by TNAP-specific shRNA. Cells were analyzed for changes in mineralization, gene expression, proliferation, apoptosis, matrix deposition and cell adhesion.Alpl(-/-) mice feature craniofacial shape abnormalities suggestive of limited anterior-posterior growth. Craniosynostosis in the form of bony coronal suture fusion is present by three weeks after birth. Alpl(-/-) mice also exhibit marked histologic abnormalities of calvarial bones and the cranial base involving growth plates, cortical and trabecular bone within two weeks of birth. Analysis of calvarial cells in which TNAP expression was suppressed by shRNA indicates that TNAP deficiency promotes aberrant osteoblastic gene expression, diminished matrix deposition, diminished proliferation, increased apoptosis and increased cell adhesion.These findings demonstrate that Alpl(-/-) mice exhibit a craniofacial skeletal phenotype similar to that seen in infants with HPP, including true bony craniosynostosis in the context of severely diminished bone mineralization. Future studies will be required to determine if TNAP deficiency and other forms of rickets promote craniosynostosis directly through abnormal calvarial cell behavior, or indirectly due to deficient growth of the cranial base.

Dataset Information

Overexpression of Fgfr2c causes craniofacial bone hypoplasia and ameliorates craniosynostosis in the Crouzon mouse.

Publications

Overexpression of <i>Fgfr2c</i> causes craniofacial bone hypoplasia and ameliorates craniosynostosis in the Crouzon mouse.

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