The trachea and esophagus are respectively respiratory and digestive organs that originate from a common foregut endoderm during development. Perturbed patterning in this endodermal tissue can result in a variety of foregut anomalies, such as tracheal agenesis (TA), esophageal atresia (EA) and tracheoesophageal fistula (TEF); however, their etiologies remain unknown.
We found that mice lacking Noggin displayed Type C EA/TEF, the most common form in humans, and notochordal defects strikingly similar to the adriamycin-induced rat EA/TEF model. In accord with esophageal atresia, Noggin-/- embryos displayed reduction in the dorsal foregut endoderm which was associated with reduced adhesion and disrupted basement membrane. However, no significant apoptosis in the Noggin-/- dorsal foregut was observed. Instead, non-notochordal, likely endodermal, cells were found in Noggin-/- notochord suggesting that Noggin function is required in the notochordal plate for its proper delamination from the dorsal foregut. Notably, ablating Bmp7 function in Noggin-/- embryos rescued EA/TEF and notochord branching defects, establishing a critical role of Noggin-mediated Bmp7 antagonism in EA/TEF pathogenesis.
In addition to the critical role of Bmp signaling in EA/TEF pathogenesis, it also plays a vital role in tracheal development. We found that conditional ablation of Bmp4 in the primitive foregut by Foxg1Cre resulted in complete loss of trachea. While tracheal specification was not affected in Bmp4-deficient foreguts, tracheal outgrowth was severely impaired. The anterior foregut domain also displayed significantly reduced epithelial and mesenchymal proliferation without apparent alteration in apoptotic cell death. While we did not observe alteration in Wnt/â-catenin signaling in the Bmp4-deficient foregut, we detected consistent reduction in the expression level of Shh, a signaling molecule known to promote cell proliferation. In line with this observation, expression of Cyclin D1, a known downstream target of Shh signaling, was also found to be reduced in Bmp4- deficient foreguts. Taken together, these findings elucidate a critical role of Bmp signaling and cell proliferation in tracheal morphogenesis and implicate potential Bmp-Shh crosstalk in anterior foregut morphogenesis.