Open AccessMidface and upper airway dysgenesis in FGFR2-craniosynostosis involves multiple tissue-specific and cell cycle effects
Author(s) -
Greg Holmes,
Courtney P. O’Rourke,
Susan M. Motch Perrine,
Na Lü,
Harm van Bakel,
Joan T. Richtsmeier,
Ethylin Wang Jabs
Publication year - 2018
Publication title -
development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.754
H-Index - 325
eISSN - 1477-9129
pISSN - 0950-1991
DOI - 10.1242/dev.166488
Subject(s) - biology , craniosynostosis , airway , dysgenesis , anatomy , surgery , medicine
Midface dysgenesis is a feature of over 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 due to 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-craniosynostosis is a complex phenotype arising from the combined effects of aberrant signaling in multiple craniofacial tissues.