ABSTRACT
Midface dysgenesis is a feature of more than 200 genetic conditions in which upper airway anomalies frequently cause respiratory distress, but its etiology is poorly understood. Mouse models of Apert and Crouzon craniosynostosis syndromes exhibit midface dysgenesis similar to the human conditions. They carry activating mutations of Fgfr2, which is expressed in multiple craniofacial tissues during development. Magnetic resonance microscopy of three mouse models of Apert and Crouzon syndromes revealed decreased nasal passage volume in all models at birth. Histological analysis suggested overgrowth of the nasal cartilage in the two Apert syndrome mouse models. We used tissue-specific gene expression and transcriptome analysis to further dissect the structural, cellular and molecular alterations underlying midface and upper airway dysgenesis in Apert Fgfr2+/S252W mutants. Cartilage thickened progressively during embryogenesis because of increased chondrocyte proliferation in the presence of Fgf2. Oral epithelium expression of mutant Fgfr2, which resulted in a distinctive nasal septal fusion defect, and premature facial suture fusion contributed to the overall dysmorphology. Midface dysgenesis in Fgfr2-related craniosynostosis is a complex phenotype arising from the combined effects of aberrant signaling in multiple craniofacial tissues.
Footnotes
Author contributions
Conceptualization: J.T.R., E.W.J.; Methodology: G.H., S.M.M.P., J.T.R., E.W.J.; Validation: G.H., S.M.M.P., N.L.; Formal analysis: G.H., C.O., S.M.M.P., N.L., H.v.B.; Investigation: G.H., C.O., S.M.M.P., N.L.; Data curation: G.H., C.O., S.M.M.P., N.L., H.v.B.; Writing - original draft: G.H., S.M.M.P.; Writing - review & editing: G.H., C.O., S.M.M.P., N.L., H.v.B., J.T.R., E.W.J.; Visualization: G.H., C.O., S.M.M.P., H.v.B.; Supervision: G.H., J.T.R., E.W.J.; Project administration: G.H., J.T.R., E.W.J.; Funding acquisition: J.T.R., E.W.J.
Funding
This work was supported by a grant from the National Institute of Dental and Craniofacial Research [R01 DE022988 to J.T.R. and E.W.J.], and in part by grants from the National Institute of Dental and Craniofacial Research [U01 DE024448 to G.H., H.v.B. and E.W.J.; R01 DE027677 to J.T.R.], the National Institute of Child Health and Human Development [P01 HD078233 to J.T.R. and E.W.J.], and the National Institutes of Health Office of Research Infrastructure Programs [S10 OD018522]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Deposited in PMC for release after 12 months.
Data availability
RNA-seq data have been deposited in GEO under the accession number GSE97828.
