Cystic Adenomatoid Malformations Are Induced by Localized FGF10 Overexpression in Fetal Rat Lung

Abstract

Fibroblast growth factor-10 (FGF10) is a mesenchymal growth factor, involved in epithelial and mesenchymal interactions during lung branching morphogenesis. In the present work, FGF10 overexpression was transiently induced in a temporally and spatially restricted manner, during the pseudoglandular or canalicular stages of rat lung development, by trans-uterine ultrasound-guided intraparenchymal microinjections of adenoviral vector encoding the rfgf10 transgene. The morphologic and histologic classification of the resulting malformations were dependent upon developmental stage and location. Overexpression of FGF10 restricted to the proximal tracheobronchial tree during the pseudoglandular phase resulted in large cysts lined by tall columnar epithelium composed primarily of Clara cells with a paucity of Type II pneumocytes, resembling bronchiolar type epithelium. In contrast, FGF10 overexpression in the distal lung parenchyma during the canalicular phase resulted in small cysts lined by cuboidal epithelial cells composed of primarily Type II pneumocytes resembling acinar epithelial differentiation. The cystic malformations induced by FGF10 overexpression appear to closely recapitulate the morphology and histology of the spectrum of human congenital cystic adenomatoid malformation (CCAM). These findings support a role for FGF10 in the induction of human CCAM and provide further mechanistic insight into the role of FGF10 in normal and abnormal lung development.

Epithelial inactivation of Yy1 abrogates lung branching morphogenesis

“…10). This mechanistic explanation is further supported by the observations that trans-uterine intraparenchymal microinjections of a vector carrying an Fgf10 transgene induce cystic lung malformations in rat fetuses that recapitulate the phenotype of human congenital cystic lung diseases (Gonzaga et al, 2008). Therefore, our work uncovers a functional cascade sequentially implicating Yy1, Shh and Fgf10 genes in lung branching coordination.…”

“…Increased Fgf10 expression appears to be a common denominator in the formation of lung cysts (Gonzaga et al, 2008). However, the reduced expression of Etv5 and Elf5 genes, encoding two transcription factors of the lung epithelium known to be under the positive control of FGF10, indicates that Yy1 acts also on gene expression independently of FGF10 signaling (Liu et al, 2003;Metzger et al, 2007).…”

Wnt ligand/Frizzled 2 receptor signaling regulates tube shape and branch-point formation in the lung through control of epithelial cell shape

“…Previous work has proposed a model for lung branch formation that includes roles for Fgf10 signaling as well as Bmp4 and Shh (Fig. 2C) (17,18). This model describes a role for Fgf10 in establishing the site of new bud formation, although recent work has questioned whether focal Fgf10 expression is required for proper branching morphogenesis to occur (19).…”

Congenital Malformations and Developmental Anomalies of the Lung

“…The etiological role of vascular abnormality has also been suggested. The molecular mechanisms which regulate normal lung development and show altered patterns of expression in CLM have been the subject of research [9][10][11]. Familial association has also been reported [12].…”