Abstract
BackgroundFibroblast growth factors (FGF) are essential key players during embryonic development. Through their specific cognate receptors (FGFR) they activate intracellular cascades, finely regulated by modulators such as Sprouty. Several FGF ligands (FGF1, 2, 7, 9, 10 and 18) signaling through the four known FGFRs, have been implicated in lung morphogenesis. Although much is known about mammalian lung, so far, the avian model has not been explored for lung studies.Methodology/Principal FindingsIn this study we provide the first description of fgf10, fgfr1-4 and spry2 expression patterns in early stages of chick lung development by in situ hybridization and observe that they are expressed similarly to their mammalian counterparts. Furthermore, aiming to determine a role for FGF signaling in chick lung development, in vitro FGFR inhibition studies were performed. Lung explants treated with an FGF receptor antagonist (SU5402) presented an impairment of secondary branch formation after 48 h of culture; moreover, abnormal lung growth with a cystic appearance of secondary bronchi and reduction of the mesenchymal tissue was observed. Branching and morphometric analysis of lung explants confirmed that FGFR inhibition impaired branching morphogenesis and induced a significant reduction of the mesenchyme.Conclusions/SignificanceThis work demonstrates that FGFRs are essential for the epithelial-mesenchymal interactions that determine epithelial branching and mesenchymal growth and validate the avian embryo as a good model for pulmonary studies, namely to explore the FGF pathway as a therapeutic target.
Highlights
Fibroblast growth factors (FGF) are secreted proteins that play an important role in multiple biological processes, such as proliferation, survival, migration and differentiation, as well as in the morphogenesis of branching organs such as the lung, kidney and pancreas, among others [1,2]
In order to analyze the expression of some members of the FGF signaling pathway in early stages of chick lung development, whole mount in situ hybridization (ISH) experiments were performed, after which representative examples of hybridized lungs from different stages of development were sectioned for histology
We found that fgf10 is expressed in the distal pulmonary mesenchyme surrounding the tip of the main bronchus (Figure 1A and D, arrows), and in the dorsal mesenchyme adjacent to the emerging secondary buds, in the three stages studied (Figure 1, dark arrowheads)
Summary
Fibroblast growth factors (FGF) are secreted proteins that play an important role in multiple biological processes, such as proliferation, survival, migration and differentiation, as well as in the morphogenesis of branching organs such as the lung, kidney and pancreas, among others [1,2]. FGF signaling depends on the activation of specific cell surface receptors (FGFR) encoded by four distinct genes, fgfr. FGFRs are single-pass transmembrane proteins with tyrosine kinase activity (RTK) which, upon ligand binding to the extracellular domain of the receptor, initiate a signal transduction cascade (Ras-MAP kinase, PI3 kinase/Akt) that results in gene expression modification [3,4]. The. Fibroblast growth factors (FGF) are essential key players during embryonic development. Fibroblast growth factors (FGF) are essential key players during embryonic development Through their specific cognate receptors (FGFR) they activate intracellular cascades, finely regulated by modulators such as Sprouty. Several FGF ligands (FGF1, 2, 7, 9, 10 and 18) signaling through the four known FGFRs, have been implicated in lung morphogenesis. Much is known about mammalian lung, so far, the avian model has not been explored for lung studies
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