Six1 transcription factor is critical for coordination of epithelial, mesenchymal and vascular morphogenesis in the mammalian lung

摘要: Six1 is a member of the six-homeodomain family transcription factors. expressed in multiple embryonic cell types and plays important roles proliferation, differentiation survival precursor cells different organs, yet its function during lung development was hitherto unknown. Herein we show that Six1(-/-) lungs are severely hypoplastic with greatly reduced epithelial branching increased mesenchymal cellularity. at distal tips tubules as well surrounding mesenchyme. expression markers, but loss progenitor markers. overexpression MLE15 vitro inhibited differentiation, increases In addition, embryos newborn mice exhibit overproliferation, decreased Fgf10 severe defects smooth muscle component bronchi major pulmonary vessels. These lead to rupture vessels mutant after birth. Treatment explants culture recombinant protein restores branching. As Shh abnormally lungs, also treated found these were competent respond continued grow culture. Furthermore, inhibition signaling cyclopamine stimulated branch This study provides first evidence for requirement coordinating Shh-Fgf10 ensure proper levels proliferation along proximodistal axis epithelial, endothelial cells. findings uncover novel essential functions critical coordinator development. We propose hence coordination vascular