Hox5Genes Regulate the Wnt2/2b-Bmp4-Signaling Axis during Lung Development

Hoxgenes are required for proper anteroposterior axial patterning and the development of several organ systems. Here, we show that all three Hox5paralogous genes play redundant roles in the developing lung. Hoxa5;Hoxb5;Hoxc5triple-mutant embryos develop severely hypoplastic lungs with reduced branching and proximal-distal patterning defects. Hox5genes are exclusively expressed in the lung mesoderm; however, defects are observed in both lung mesenchyme and endodermally derived epithelium, demonstrating that Hox5genes act to regulate mesodermal-epithelial crosstalk during development. We show that Hox5loss of function leads to loss of Wnt2/2bexpression in the distal lung mesenchyme and the downregulation of previously identified downstream targets of Wnt2/2bsignaling, including Lef1, Axin2, and Bmp4. Wnt2/2b-enriched media rescue proper Sox2/Sox9 patterning and restore Bmp4expression in Hox5triple-mutant lung explants. Taken together, these data show that Hox5genes are key upstream mesenchymal regulators of the Wnt2/2b-Bmp4-signaling axis critical for proper lung patterning.