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Emergent Properties of Facial Morphogenesis Regulated by Fgf Signaling

Craniosynostosis is a severe disorder that may be caused by activating mutations in Fibroblast growth factor receptors (FgfRs) that affects development of the skull and is characterized by premature fusion of the cranial sutures. In addition to dysmorphology of the skull, affected individuals also have facial dysmorphology. We have previously used an avian model to explore the role that a disease‐causing allele of FgfR2 (FgfR2C278F) plays in producing malformations of the middle and upper face at early stages of development. In that work we observed a wider midface, which resembles what is observed in human patients, and this was directly related to decreased cell proliferation and a disrupted net polarization of the mesenchymal cells in the growing facial primordia. We have extended this work by examining the role of the Map kinase, PLC‐gamma, and PI3K pathways downstream of Fgf signaling in producing facial dysmorphology, as well as directly blocking FgfR activation. We implanted beads soaked in small molecular inhibitors (MEK1/2: U0126, PLC‐gamma: U‐73122, PI3K: LY 294002, FgfR activation: SU5402) into the right side of the developing avian face at HH22 and examined morphological and cellular outcomes at various times of development. First, we determined that each inhibitor substantially and specifically down‐regulated its respective pathway using immunohistochemistry to assess expression of down‐stream targets of activation of each pathway. We then determined that each pathway significantly reduced cell proliferation and altered cell polarization in the mesenchyme. Blocking each pathway also created severe craniofacial malformations that were observed at early and late time points. There are many inputs to each of these pathways, and our data suggest that each participate in regulation of a similar set of cellular processes that contribute to the emergence of morphogenetic processes in facial development.