Function of Wnt/beta-Catenin signaling in developing mesenchyme

Canonical Wnt/beta-Catenin signaling has diverse roles in organ development and pathological processes by regulating cell proliferation, survival and fate determination. Most studies on canonical Wnt/beta-Catenin signaling have focused on epithelial cells. The function of canonical Wnt/beta-Catenin in developing mesenchyme is poorly understood. Here we analyzed the function of canonical Wnt/beta-Catenin signaling in developing lung and pharyngeal apparatus mesenchyme. We used mouse model systems to conditionally inactivate beta-Catenin gene function with a mesenchymal specific cre recombinase allele. In developing lung mesenchyme we showed that mesenchymal canonical Wnt/beta-Catenin signaling is essential for mesenchymal cell proliferation and regulates the Fgf responsiveness of mesenchyme through regulation of Fgfrs expression. The major finding of this study is that both Fgf and Wnt signaling pathways are critical to sustain mesenchymal growth and coordinate epithelial morphogenesis during the pseudoglandular stage of lung development. In developing pharyngeal arch mesenchyme, canonicat Wnt/beta-Catenin signaling negatively regulates Tbx1 expression and mesenchymal inactivation of beta-Catenin caused abnormalities resembling DiGeorge syndrome. Also, in a heterozygous Fgf8 or Tbx1 genetic background, ectopic activation of Wnt/beta-Catenin signaling caused an increased incidence and severity of DiGeorge syndrome phenotypes. Thus, the major finding of this study is that we identified canonical Wnt/beta-Catenin signaling as a critical upstream regulator of Tbx1. These data suggest that factors that affect Wnt/beta-Catenin signaling could modify the incidence and severity of DiGeorge syndrome.