Mechanisms of FGF‐Mediated Morphogenesis

Abstract

Signaling by Fibroblast growth factors (Fgf) regulates many aspects of vertebrate development. During facial development, Fgf signaling helps regulate morphogenetic processes that control formation of the jaw skeleton. Using an Fgf8 allelic series of mice with graded levels of Fgf8 expression, we have demonstrated the requirement for Fgf8 signaling during facial development. However, the cellular and molecular mechanisms that Fgf signaling utilizes to direct morphogenesis are less clear. To address this, we turned to the chick system and infected embryos with retroviruses that encode either Fgf8, or a constitutively activated FgfR2, which causes craniosynostosis in humans. We determined that activation of the Fgf pathway led to mid‐facial hypoplasia accompanied by widening of the mid‐face. These morphologies were associated with decreased cell proliferation and increased expression of Sprouty's, Dusp's, and Spred's. We also observed that neural crest cells are polarized with respect to the sub‐cellular localization of the Golgi apparatus, and after activation of the Fgf pathway with either virus this polarity was disrupted. This disruption was associated with the extent of malformation present in the embryos. The Golgi apparatus is located adjacent to the nucleus in the leading edge of moving cells suggesting that oriented cell movement is required for normal morphogenesis. We are now testing how directed cell movements may contribute to morphogenetic processes, and our preliminary data suggest that forces exerted on the extracellular matrix may play a role in this process. In summary, a series of cellular processes such as proliferation and polarization appear to contribute to the emergent properties of developing systems during facial morphogenesis.