Investigation of the roles of fibroblast growth factor signaling in lung branching morphogenesis.

摘要

Few biological processes are as ancient or as obligate for life as respiration. Organisms that live on land are able to do so because they have evolved a fascinating and complex organ for respiration: the lung. The lung is composed of a network of epithelial tubules that arise through a reiterative branching process. Ramification of these branches ultimately generates the respiratory tree, creating an expansive surface for gas exchange. Because normal lung function relies heavily on proper branch formation, a significant amount of research has been devoted to understanding the processes that drive branching morphogenesis. Despite these efforts, the molecular mechanisms that underlie these processes remain largely uncharacterized. To address this question, I have utilized the mouse lung as a model of mammalian lung development to examine how conserved signaling pathways contribute to epithelial branching morphogenesis.;Genetic and molecular analyses in mouse indicate that conserved gene families play important roles in lung development. Fibroblast Growth Factors (FGFs) are one such family. FGF10 signaling through FGF receptor 2 (FGFR2) is required for lung initiation, as demonstrated by the absence of a lung in mice carrying null alleles of either Fgf10 or Fgfr2b. However, the severity of these phenotypes precludes examination of possible roles for these two factors in later branching events. Through conditional gene inactivation, my work demonstrates that both Fgf10 and Fgfr2 are essential for normal branching morphogenesis. Inactivation of Fgf10 in the lung mesenchyme or Fgfr2 in the lung epithelium resulted in smaller lungs with reduced epithelial branching. Analysis of these mutants revealed that expression levels or patterns of several signaling factors known to be important for lung development were altered due to decreased FGF signaling. In addition, we found that a proximal lung epithelial marker was expanded posteriorly in both mutants. This finding suggests that the FGF10-FGFR2 pathway is required for normal proximal-distal patterning of the lung, a result that has not been demonstrated previously. In summary, this thesis provides insight into how FGF signaling functions to regulate branching morphogenesis and therefore normal lung development.