Abstract
BackgroundCystic fibrosis transmembrane conductance regulator (CFTR) was shown previously to modify stretch induced differentiation in the lung. The mechanism for CFTR modulation of lung development was examined by in utero gene transfer of either a sense or antisense construct to alter CFTR expression levels.The BAT-gal transgenic reporter mouse line, expressing β-galactosidase under a canonical Wnt/β-catenin-responsive promoter, was used to assess the relative roles of CFTR, Wnt, and parathyroid hormone-related peptide (PTHrP) in lung organogenesis. Adenoviruses containing full-length CFTR, a short anti-sense CFTR gene fragment, or a reporter gene as control were used in an intra-amniotic gene therapy procedure to transiently modify CFTR expression in the fetal lung.ResultsA direct correlation between CFTR expression levels and PTHrP levels was found. An inverse correlation between CFTR and Wnt signaling activities was demonstrated.ConclusionThese data are consistent with CFTR participating in the mechanicosensory process essential to regulate Wnt/β-Catenin signaling required for lung organogenesis.
Highlights
Cystic fibrosis transmembrane conductance regulator (CFTR) was shown previously to modify stretch induced differentiation in the lung
These data are consistent with CFTR participating in the mechanicosensory process essential to regulate Wnt/β-Catenin signaling required for lung organogenesis
Recombinant adenoviruses with either eGFP (AdCMVeGFP; control), CFTR (Av1CF2; [12,13,15]), or antisense CFTR
Summary
Cystic fibrosis transmembrane conductance regulator (CFTR) was shown previously to modify stretch induced differentiation in the lung. The mechanism for CFTR modulation of lung development was examined by in utero gene transfer of either a sense or antisense construct to alter CFTR expression levels. Several laboratories have demonstrated that this complex process involves the promotion of mechanical stretch [1,2,3,4]. Muscle contractions of the large airways compress amniotic fluid in the fetal lung generating a pressure gradient that is converted to biochemical signals necessary for cell differentiation. Mechanicosensing and the genes involved, are less well known Sensing molecules such as integrins, ion channels, and kinase-linked receptors have been implicated in changes in gene expression related to stretch [6]. Most of the evidence from these studies implicates vascular responses to stretch in hemodynamic stasis, little is known about these sensors in fetal organogenesis
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