FGF signaling in the epithelium and mesenchyme plays important functions during lung development. A member of the FGF family, FGF10 is a master player in the signaling network mediating epithelial-mesenchymal interactions in the lung. However, the specific mechanisms of action of FGF10 on the epithelium as well as the epithelial targets downstream of FGF10 in vivo are just emerging. In addition, how FGF10 impacts the formation of the smooth muscle cells, which are essential for alveolarization and lung function, is so far unknown. Our preliminary data indicate that we can use an Fgf10 hypomorphic mouse to decipher the role of FGF10 in lung development. Our preliminary results indicate that a) FGF10 signaling controls (-catenin signaling in the epithelium. b) FGF10 controls the amplification of the epithelial progenitors as well as maintains them in a "distal-like" phenotype and c) FGF10 signaling to the epithelium controls the formation of the alveolar smooth muscle cell progenitors. Furthermore, we recently reported that the pathological activation of an FGF10/FGFR2b autocrine feedback loop in the mesenchyme is responsible for the lung defects observed in a mouse model of Apert syndrome (De Langhe et al., 2006). Apert patients also exhibit many lung defects including fusion of tracheal cartilage, pulmonary aplasia, absent accessory lobe and defective interlobular septation. Our results also show that modulation of Fgf10 expression in this mouse model of Apert syndrome rescues the observed lung defects. This mouse Apert model will therefore allow us to determine how FGF signaling in the mesenchyme controls the differentiation and prevents the differentiation of the smooth muscle cell progenitors. Hypothesis: FGF10 is critical to control mesenchymal differentiation during normal and pathological lung development.
Aim 1 : To determine the role of epithelial FGF10 signaling during lung development using a newly described Fgf10 hypomorphic mouse.
Aim 2 : To determine the role of mesenchymal FGF signaling during lung development using a mouse model of Apert syndrome where Fgfr2b is ectopically expressed in the mesenchyme. Health Relevance: FGF10 is a key factor during lung development. Understanding the impact of FGF10 signaling on the proliferation and differentiation of the epithelium and mesenchyme throughout lung development in physiological and pathological situations may suggest novel strategies to rescue the lung dysplasia phenotype in patients with Apert syndrome as well as to rescue lung development in diseases of prematurity such as broncho-pulmonary dysplasia or emphysema and lung fibrosis in older patients.FGF signaling in the epithelium and mesenchyme plays important function during lung development.
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