Mouse Models of Syndromic Craniosynostosis

Lee, Kevin K.L.; Stanier, Philip; Pauws, Erwin

doi:10.1159/000491004

Cited by 23 publications

(22 citation statements)

References 153 publications

(229 reference statements)

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“…Mice provide an excellent model for the study of suturogenesis, and numerous mutant mouse models reproduce the phenotypes of human mutations ( Holmes, 2012 ; Lee et al, 2019b ). Twist1 and Fgfr2 are important in regulating the balance between maintenance of SM and osteogenic differentiation.…”

Section: Introductionmentioning

confidence: 99%

Integrated Transcriptome and Network Analysis Reveals Spatiotemporal Dynamics of Calvarial Suturogenesis

et al. 2020

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SUMMARY Craniofacial abnormalities often involve sutures, the growth centers of the skull. To characterize the organization and processes governing their development, we profile the murine frontal suture, a model for sutural growth and fusion, at the tissue- and single-cell level on embryonic days (E)16.5 and E18.5. For the wild-type suture, bulk RNA sequencing (RNA-seq) analysis identifies mesenchyme-, osteogenic front-, and stage-enriched genes and biological processes, as well as alternative splicing events modifying the extracellular matrix. Single-cell RNA-seq analysis distinguishes multiple subpopulations, of which five define a mesenchymeosteoblast differentiation trajectory and show variation along the anteroposterior axis. Similar analyses of in vivo mouse models of impaired frontal suturogenesis in Saethre-Chotzen and Apert syndromes, Twist1 +/− and Fgfr2 +/S252W , demonstrate distinct transcriptional changes involving angiogenesis and ribogenesis, respectively. Co-expression network analysis reveals gene expression modules from which we validate key driver genes regulating osteoblast differentiation. Our study provides a global approach to gain insights into suturogenesis.

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Section: Introductionmentioning

confidence: 99%

Integrated Transcriptome and Network Analysis Reveals Spatiotemporal Dynamics of Calvarial Suturogenesis

et al. 2020

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“…In the developing mouse cranial vault, Fgfr2 is expressed in the osteogenic fronts of the calvarial bones, but the specific cellular localisation of the different FGFR2 isoforms remains elusive due to their high sequence homology ( Johnson et al, 2000 ; Iseki et al, 1997 ). FGFR2c function is commonly associated with craniofacial and skeletal development, as genetic mutation in mouse models leads to a series of craniofacial malformations and additional skeletal dysmorphology ( Lee et al , in press). Deletion of the FGFR2c isoform ( Fgfr2c null ) results in skeletal hypoplasia and craniosynostosis owing to imbalances in osteoprogenitor proliferation and differentiation in the endochondral and intramembranous skeleton ( Eswarakumar et al, 2002 ).…”

Section: Introductionmentioning

confidence: 99%

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

Lee

Peskett

Quinn

et al. 2018

Disease Models &Amp; Mechanisms

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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 pathogenic FGFR2c signalling by studying the effects of Fgfr2c overexpression. Conditional overexpression of Fgfr2c (R26RFgfr2c;βact) results in craniofacial hypoplasia as well as microtia and cleft palate. Contrary to Fgfr2cnull and Fgfr2cC342Y, Fgfr2c overexpression is insufficient to drive onset of craniosynostosis. Examination of the MAPK/ERK pathway in the embryonic sutures of Fgfr2cC342Y and R26RFgfr2c;βact mice reveals that both mutants have increased pERK expression. The contrasting phenotypes between Fgfr2cC342Y and R26RFgfr2c;βact mice prompted us to assess the impact of the Fgfr2c overexpression allele on the Crouzon mouse (Fgfr2cC342Y), 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 Fgfr2cC342Y 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.

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“…The copyright holder for this preprint this version posted February 27, 2021. ; https://doi.org/10.1101/2021.02.27.433115 doi: bioRxiv preprint Gene enrichment analysis. Lists of 96 human and 31 mouse genes associated with craniosynostosis and subsets of genes associated with coronal synostosis (5,7,22,23) (SI Appendix, Table S2) were tested for significant (p ≤ 0.05) gene set enrichment against the single cell CS populations, determined by scRNA-seq analysis using Fisher's exact test and using Bonferroni correction for multiple comparisons. This method was also used to match the single cell CS populations identified at E16.5 with those identified at E18.5.…”

Section: Micementioning

confidence: 99%

Single-cell analysis identifies a key role forHhipin murine coronal suture development

Holmes¹,

Gonzalez‐Reiche

Saturne³

et al. 2021

Preprint

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Craniofacial development depends on proper formation and maintenance of sutures between adjacent bones of the skull. Within sutures, bone growth occurs through proliferation and differentiation of osteoprogenitors to osteoblasts within the osteogenic front at the edge of each bone, and suture mesenchyme maintains the separation between them. Many genes have been found that cause suture dysgenesis when mutated, particularly of the coronal suture. Such genes are largely studied in isolation, and there is little understanding of the overall transcriptional programs within the suture or of the cell populations in which these programs are organized. We performed single-cell and bulk RNA-seq analyses of the murine coronal suture during embryonic development. Replicate libraries at E16.5 and E18.5 were analyzed. We identified 14 cell type populations when both ages were analyzed together. Seven populations at E16.5 and nine at E18.5 comprised the suture mesenchyme, osteogenic fronts, osteoblasts, and associated cell types. We found a distinct coronal suture mesenchyme population at both ages compared to other neurocranial sutures, which was marked by expression of Hhip, an inhibitor of hedgehog signaling. We examined Hhip-/- mice and found a previously unrecognized coronal suture phenotype. At E18.5, Hhip-/- frontal and parietal bones lack the overlap typical of the WT coronal suture. The osteogenic fronts are closely apposed and the suture mesenchyme is depleted, demonstrating that Hhip function is required for normal coronal suture development. Our transcriptomic approach provides a rich resource for further discoveries of potential normal and abnormal developmental relevance.

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Mouse Models of Syndromic Craniosynostosis

Cited by 23 publications

References 153 publications

Integrated Transcriptome and Network Analysis Reveals Spatiotemporal Dynamics of Calvarial Suturogenesis

Integrated Transcriptome and Network Analysis Reveals Spatiotemporal Dynamics of Calvarial Suturogenesis

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

Single-cell analysis identifies a key role forHhipin murine coronal suture development

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