Formation and differentiation of multiple mesenchymal lineages during lung development is regulated by β-catenin signaling

Background. The role of ß-catenin signaling in mesodermal lineage formation and differentiation has been elusive. Methodology. To define the role of B-catenin signaling in these processes, we used a Dermol^Cre/+;(Twist2)^Cr+e line to target a floxed β-catenin allele, throughout the embryonic, mesenchyme. Strikingly, the Dermol^Cre/; β-catenin^l/- conditional Knock Out embryos largely phenocopy Pitx1^-/-; Pitx2^-/- double knockout embryos, suggesting that B-catenin signaling in the messenchyme depends mostly on the PITX family transcription factors. We have dissected this relationship further in the developing lungs and find that mesenchymal deletion of β-catenin differentially affects two major mesenchymal lineages. The amplification but not differentiation of Fgf10-expressing parabronchial smooth muscle progenitor cells is drastically reduced. In the angioblast-endothelial lineage, however, only differentiation into mature endothelial cells is impaired. Conclusion. Taken together these findings reveal a hierarchy of gene activity involving ß-catenin and PITX, as important regulators of mesenchymal cell proliferafion and diffefentiation.