The objective of this project is to understand how respiratory progenitors in the primitive foregut and theearly lung are spatially organized to later form distinct regions of the respiratory system. Little is known aboutthe cellular and molecular events that lead to segregation and expansion of respiratory progenitors duringearly lung and tracheal development. Studies in a number of biological systems from Drosophila to mammalsimplicate signaling by Fgf and Notch in these functions. Notch works via cell-cell interactions to control cellfate decisions, establishment of asymmetries, and timing of differentiation. FGF and Notch interact duringformation of several developing structures.Here we present preliminary evidence that Notch pathway components are present and active in the lungand tracheal primordia. We show that disruption of Notch in vitro alters morphogenetic boundaries andinduces ectopic budding in the lung epithelium. Furthermore, our data suggest a mechanism in which Fgf 10controls Notch activity via its antagonist Numb during epithelial morphogenesis. We hypothesize that at theonset of lung development respiratory progenitors in the respiratory field of the foregut are expanded andprogressively patterned by mechanisms regulated by FgflO-Notch signaling, and that likely involves celladhesion molecules. We propose that FgflO-Notch interactions contribute to control boundaries andgenerate asymmetric signaling that results in the appearance of distinct regions of the respiratory tract. Thus,in this Project we will:
(Aim 1) characterize the establishment of the Notch pathway in the early lung, and theeffects of its global disruption in vitro;
(Aim 2) define the role of Notch and Numb by selectively altering thesesignals in respiratory progenitor cells in vivo;
(Aim3) characterize the mechanisms by which FgflO-Notchcontrol expansion and patterning of respiratory progenitor during lung morphogenesis.These studies will provide information about basic mechanisms by which Notch and Fgf signalinginfluence cellular activities in respiratory progenitors of the embryonic lung. However, both Fgf and Notchsignaling have been also implicated in multiple processes postnatally, including stem cell maintenance andtumorigenesis. Thus, our results are likely to have an impact in the understanding of how these moleculesmay act in lung repair and cancer.
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