Osr1 functions downstream of Hedgehog pathway to regulate foregut development

During early fetal development, paracrine Hedgehog (HH) ligands secreted from the foregut epithelium activate Gli transcription factors in the surrounding mesenchyme to coordinate formation of the respiratory system, digestive track and the cardiovascular network. Although disruptions to this process can lead to devastating congenital defects, the underlying mechanisms and downstream targets, are poorly understood. We show that the zinc finger transcription factor Osrl is a novel HH target as Osrl expression in the foregut mesenchyme depends on HH signaling and the effector of HH pathway Gli3 binds to a conserved genomic loci near Osrl promoter region. Molecular analysis of mouse germline Osrl mutants reveals multiple functions of Osrl during foregut development. Osrl mutants exhibit fewer lung progenitors in the ventral foregut. Osr is then required for the proper branching of the primary lung buds, with mutants exhibiting miss-located lung lobes. Finally, Osrl is essential for proper mesenchymal differentiation including pulmonary arteries, esophageal and tracheal smooth muscle as well as tracheal cartilage rings. Tissue specific conditional knockouts in combination with lineage tracing indicate that Osrl is required cell autonomously in the foregut mesenchyme. We conclude that Osrl is a novel downstream target of HH pathway, required for lung specification, branching morphogenesis and foregut mesenchymal differentiation.