Signaling through BMP receptors promotes respiratory identity in the foregut via repression of SOX2

The mammalian foregut gives rise to the dorsally-located esophagus and stomach, and the ventrally-located trachea and lung. Proper patterning and morphogenesis of the common foregut tube and its derived organs is essential for viability of the organism at birth. Previous studies suggest that bone morphogenetic protein (BMP) signaling is important for early stages of respiratory development. However, its precise role in this process remains unclear. Here we show that conditional inactivation of BMP Type I receptor genes Bmpr1a and Bmpr1b (Bmpr1a;b) in the ventral endoderm leads to tracheal agenesis and ectopic primary bronchi. Molecular analyses of these mutants reveal a reduction of ventral endoderm marker NKX2.1 along with an expansion of dorsal markers SOX2 and P63 in the prospective trachea and primary bronchi. Previous studies show that activation of WNT/ß-catenin signaling can induce respiratory fate ectopically. Our genetic results indicate that this promotion of respiratory fate is dependent on Bmpr1a;b. Furthermore, we find that inactivation of Sox2 in Bmpr1a;b mutants, while does not suppress ectopic lung budding, rescues trachea formation and NKX2.1 expression. Together, our data suggest that signaling through BMPR1A;B performs at least two roles in early respiratory development: first, it promotes tracheal formation through repression of Sox2, and second, it restricts the site of lung bud initiation.