Aberrant Bmp signaling and notochord delamination in the pathogenesis of esophageal atresia.

Li Y, Litingtung Y, Ten Dijke P, Chiang C
Dev Dyn. 2007 236 (3): 746-54

PMID: 17260385 · DOI:10.1002/dvdy.21075

Human foregut malformation known as esophageal atresia with tracheoesophageal fistula (EA/TEF) occurs in 1 in 4,000 live births with unknown etiology. We found that mice lacking Noggin (Nog(-/-)) 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, Nog(-/-) embryos displayed reduction in the dorsal foregut endoderm, which was associated with reduced adhesion and disrupted basement membrane. However, significant apoptosis in the Nog(-/-) dorsal foregut was not observed. Instead, non-notochordal, likely endodermal, cells were found in Nog(-/-) notochord, suggesting that Noggin function is required in the notochordal plate for its proper delamination from the dorsal foregut. Notably, ablating Bmp7 function in Nog(-/-) embryos rescued EA/TEF and notochord branching defects, establishing a critical role of Noggin-mediated Bmp7 antagonism in EA/TEF pathogenesis.

MeSH Terms (17)

Animals Bone Morphogenetic Protein 7 Bone Morphogenetic Proteins Carrier Proteins Digestive System Abnormalities Esophageal Atresia Immunohistochemistry In Situ Hybridization Mice Mice, Inbred C57BL Mice, Inbred ICR Mice, Knockout Models, Biological Notochord Rats Signal Transduction Transforming Growth Factor beta

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