Cano E, Carmona R, Muñoz-Chápuli R. Wt1-expressing progenitors contribute to multiple tissues in the developing lung. Am J Physiol Lung Cell Mol Physiol 305: L322-L332, 2013. First published June 28, 2013 doi:10.1152 doi:10. /ajplung.00424.2012velop from paired endodermal outgrowths surrounded by a mesodermal mesenchyme. Part of this mesenchyme arises from epithelialmesenchymal transition of the mesothelium that lines the pulmonary buds. Previous studies have shown that this mesothelium-derived mesenchyme contributes to the smooth muscle of the pulmonary vessels, but its significance for lung morphogenesis and its developmental fate are still little known. We have studied this issue using the transgenic mouse model mWt1/IRES/GFP-Cre (Wt1 cre ) crossed with the Rosa26R-EYFP reporter mouse. In the developing lungs, Wt1, the Wilms' tumor suppressor gene, is specifically expressed in the embryonic mesothelium. In the embryos obtained from the crossbreeding, the Wt1-expressing cell lineage produces the yellow fluorescent protein (YFP), allowing for colocalization with differentiation markers. Wt1 cre -YFP cells were very abundant from the origin of the lung buds to postnatal stages, contributing significantly to pulmonary endothelial and smooth muscle cells, bronchial musculature, tracheal and bronchial cartilage, as well as CD34 ϩ fibroblast-like interstitial cells. Thus Wt1 cre -YFP mesenchymal cells show the very same differentiation potential as the splanchnopleural mesenchyme surrounding the lung buds. FSP1 ϩ fibroblast-like cells were always YFP Ϫ ; they expressed the common leukocyte antigen CD45 and were apparently recruited from circulating progenitors. We have also found defects in pulmonary development in Wt1 Ϫ/Ϫ embryos, which showed abnormally fused lung lobes, round-shaped and reduced pleural cavities, and diaphragmatic hernia. Our results suggest a novel role for the embryonic mesothelium-derived cells in lung morphogenesis and involve the Wilms' tumor suppressor gene in the development of this organ. pulmonary development; coelomic epithelium; mesothelium; Wilms' tumor suppressor gene THE DEVELOPMENT OF THE RESPIRATORY system was a key evolutionary event for the air-breathing vertebrates. Lungs arose as specialized endodermal sacs from the digestive tract, and this phylogenetic origin is recapitulated in lung ontogeny. The contribution of mesodermal cells to the endodermal structures is essential for pulmonary development and function. In mouse embryos, the lung primordium sprouts from the ventral foregut by embryonic day (E) 9.5. It consists of a simple tube of endodermal epithelium surrounded by mesenchyme derived from the splanchnic mesoderm and lined by a layer of mesothelium. This primary tube branches in the pair of pulmonary sacs (reviewed in Ref. 17).