Hox5 Genes Regulate the Wnt2/2b-Bmp4-Signaling Axis during Lung Development

• All three Hox5 paralogous genes play redundant roles in the developing lung
• Hox5 triple mutants exhibit severely hypoplastic lungs with altered proximal-distal patterning
• The loss of Hox5 function leads to the loss of mesenchymal Wnt2/2b expression
• The addition of Wnt2/2b ligand rescues Hox5 phenotypes, demonstrating sufficiency

SummaryHox genes are required for proper anteroposterior axial patterning and the development of several organ systems. Here, we show that all three Hox5 paralogous genes play redundant roles in the developing lung. Hoxa5;Hoxb5;Hoxc5 triple-mutant embryos develop severely hypoplastic lungs with reduced branching and proximal-distal patterning defects. Hox5 genes are exclusively expressed in the lung mesoderm; however, defects are observed in both lung mesenchyme and endodermally derived epithelium, demonstrating that Hox5 genes act to regulate mesodermal-epithelial crosstalk during development. We show that Hox5 loss of function leads to loss of Wnt2/2b expression in the distal lung mesenchyme and the downregulation of previously identified downstream targets of Wnt2/2b signaling, including Lef1, Axin2, and Bmp4. Wnt2/2b-enriched media rescue proper Sox2/Sox9 patterning and restore Bmp4 expression in Hox5 triple-mutant lung explants. Taken together, these data show that Hox5 genes are key upstream mesenchymal regulators of the Wnt2/2b-Bmp4-signaling axis critical for proper lung patterning.

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