Although disruption of retinoic acid (RA) signaling in the embryo is known to result in congenital abnormalities in multiple organs, including the respiratory tract, little is known about the mechanisms by which endogenous RA regulates lung development. The goal of this project is to investigate the RA-dependent signaling events during primary lung bud induction. Our studies indicate that RA activity is essential in the foregut to initiate lung bud morphogenesis. We have evidence that disruption of RA signaling in the foregut prevents local expression of fibroblast growth factor 10 (FGF10) selectively in the lung field and blocks lung morphogenesis. Global analysis of RA sufficient and deficient foreguts revealed that decreased RA activity was associated with abnormal activation of the TGF beta (TGFb) pathway and decreased expression of putative transcriptional regulators of FGF10. Interestingly, TGFb regulates FGF10 expression in several biological systems. Thus, an RA-dependent network that includes inducers of FGF10 and repressers of TGFb signaling may act selectively in the lung field during formation of the lung primordium. Here we propose to further explore these observations by investigating the mechanisms by which RA -TGFb - FGF10 interact, favoring the hypothesis that RA inhibition of TGFb signaling allows FGF10 expression and bud formation in the lung field (Aims 1 and 2). We will also study the role of signaling by specific RA receptors (RAR) during lung bud initiation (Aim 3). This will be accomplished by characterizing early lung development using genetic models of RA deficiency and RAR isotype selective retinoids. These studies will provide novel insights into the mechanisms by which RA controls early lung development. Relevance for public health: Deficiency or excess of Vitamin A and its derivatives retinoids affects critically formation of the lung and other organs. The research proposed here will help to understand how some congenital lung defects occur, and how retinoids regulate normal development. ? ? ? ? ? ?
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