The goal of this project is to determine how fibroblast growth factors (FGFs) act individually or in concert with pattern-related genes to influence lung pattern formation and epithelial cell dedifferentiation during lung development. We will focus specifically on members of the FGF family and receptors (FGFRs), and we will study their relationship to pattern-related molecules of the Hox gene family and Sonic hedgehog (Shh), as they interact to regulate airway branching and epithelial cell differentiation in the embryonic lung. These genes are all expressed in the developing lung, and likely play an important, interactive role in lung development. We hypothesize that FGFs, Shh and Hox genes form a network of signals that results in regional control of lung patterning and epithelial differentiation. We will examine their interactions using both in vitro and in vivo model systems that include lung organ cultures, cell culture systems and transgenic animals. We propose three specific aims: (1) to study how FGFs and receptors regulate embryonic lung epithelial cell proliferation and differentiation. This will be accomplished by performing a careful evaluation of the timing and sites of FGF/FGFR expression during lung development, determining regional differences in response to exogenous FGFs (pattern of growth and differentiation) on mesenchyme-free lung and tracheal epithelial cultures, and by blocking specific FGF- FGFR interactions in cultured embryonic lung buds and in lungs of transgenic animals; (2) to determine the extent of FGF interactions with Hox genes and their role in lung development;; (3) to explore the role of Shh by overexpressing or blocking Shh in epithelial lung organ cultures, cell culture and in transgenic animals. We will study how Shh influences FGF and Hox gene expression in these systems. We will also study how pattern formation and differentiation are altered by changes in Shh expression in vitro and in vivo. These studies will provide new information about key regulatory events in epithelial-mesenchymal interactions that guide development of the embryonic lung.
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