title: Quantification of shape and cell polarity reveals a novel mechanism underlying malformations resulting from related FGF mutations during facial morphogenesis.
abstract: Fibroblast growth factor (FGF) signaling mutations are a frequent contributor to craniofacial malformations including midfacial anomalies and craniosynostosis. FGF signaling has been shown to control cellular mechanisms that contribute to facial morphogenesis and growth such as proliferation, survival, migration and differentiation. We hypothesized that FGF signaling not only controls the magnitude of growth during facial morphogenesis but also regulates the direction of growth via cell polarity. To test this idea, we infected migrating neural crest cells of chicken embryos with  replication-competent avian sarcoma virus expressing either FgfR2(C278F), a receptor mutation found in Crouzon syndrome or the ligand Fgf8. Treated embryos exhibited craniofacial malformations resembling facial dysmorphologies in craniosynostosis syndrome. Consistent with our hypothesis, ectopic activation of FGF signaling resulted in decreased cell proliferation, increased expression of the Sprouty class of FGF signaling inhibitors, and repressed phosphorylation of ERK/MAPK. Furthermore, quantification of cell polarity in facial mesenchymal cells showed that while orientation of the Golgi body matches the direction of facial prominence outgrowth in normal cells, in FGF-treated embryos this direction is randomized, consistent with aberrant growth that we observed. Together, these data demonstrate that FGF signaling regulates cell proliferation and cell polarity and that these cell processes contribute to facial morphogenesis.
authors.affiliation: Department of Orthopedic Surgery, Orthopedic Trauma Institute, San Francisco General Hospital, University of California, San Francisco, CA, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Nathan M
authors.initials: NM
authors.lastname: Young
authors.forename: Stephen
authors.initials: S
authors.lastname: Tropp
authors.forename: Diane
authors.initials: D
authors.lastname: Hu
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Xu
authors.forename: Benedikt
authors.initials: B
authors.lastname: Hallgrímsson
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Marcucio
mesh_terms: D000818:Animals; D016764:Cell Polarity / Q000235:genetics*; D049109:Cell Proliferation; D048430:Cell Shape / Q000235:genetics; D002642:Chick Embryo; D005145:Face; D051524:Fibroblast Growth Factor 8 / Q000235:genetics / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008445:Maxillofacial Development / Q000235:genetics*; D009024:Morphogenesis / Q000235:genetics*; D009154:Mutation; D009432:Neural Crest / Q000166:cytology / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C496456:FGF8 protein, human; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D051497:Receptor, Fibroblast Growth Factor, Type 2
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