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

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Boston University
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Cushing, Leah; Costinean, Stefan; Xu, Wei et al. (2015) Disruption of miR-29 Leads to Aberrant Differentiation of Smooth Muscle Cells Selectively Associated with Distal Lung Vasculature. PLoS Genet 11:e1005238
Mori, Munemasa; Mahoney, John E; Stupnikov, Maria R et al. (2015) Notch3-Jagged signaling controls the pool of undifferentiated airway progenitors. Development 142:258-67
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