Aberrant Bmp signaling and notochord delamination in the pathogenesis of esophageal atresia.
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.
Li
Yina
Y
Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Litingtung
Ying
Y
Ten Dijke
Peter
P
Chiang
Chin
C
D000818:Animals; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D004065:Digestive System Abnormalities / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004933:Esophageal Atresia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008954:Models, Biological; D009672:Notochord / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000099176:Noggin Protein
D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D016212:Transforming Growth Factor beta; D000099176:Noggin Protein; C525819:BMP7 protein, human; C525821:Bmp7 protein, rat