Abstract
Background
The organogenesis of esophageal atresia with tracheoesophageal fistula remains unclear.
We have previously demonstrated that the fistula tract develops from a trifurcation
of the embryonic lung bud and displays pulmonary lineage traits. Unlike the lung,
the fistula grows without branching. Bone morphogenetic proteins (BMPs) are known
to be important in lung branching. We studied possible BMP signaling defects as a
potential cause for the absence of branching in the fistula tract.
Methods
Adriamycin was administered to pregnant rats on days 6-9 of gestation to induce tracheoesophageal
fistula. Microdissection was performed at E13 and E17 isolating the foregut. Tissues
were analyzed using immunohistochemistry for BMP ligand (BMP2, BMP4, BMP7) and receptor
(BMPRIA, BMPRIB, BMPRII) expression.
Results
Immunohistochemistry revealed the presence of all 3 BMP ligands at E13, localized
specifically to the esophageal mucosa but absent in the fistula and lung. At E17,
the ligands were again present in the esophageal mucosa, and additionally in the fistula
tract mucosa, but remained absent in the lung. At E17, all of the BMP receptors were
also localized to the luminal surface of esophagus and fistula. However, in the lung
epithelium, only BMPRII was found, whereas BMPRIA and BMPRIB remained absent.
Conclusions
The normal expression pattern of BMP4 was increased at the branch tips and low between
branches. Among other results, we show here a constant expression level of BMP ligands
throughout the entire epithelium of the fistula tract. This diffuse expression suggests
defective BMP signaling in the fistula tract and explains its nonbranching phenotype.
Index words
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References
- Teratogenicity of adriamycin and daunomycin in the rat and rabbit.Teratology. 1978; 17: 151-157
- Histopathologic study of esophageal atresia and tracheoesophageal fistula in an animal model.J Pediatr Surg. 1997; 32: 12-14
- A new rodent experimental model of esophageal atresia and tracheoesophageal fistula: preliminary report.J Pediatr Surg. 1996; 31: 498-502
- Esophageal atresia with tracheoesophageal fistula: suggested mechanism in faulty organogenesis.J Pediatr Surg. 1999; 34: 204-208
- Complete discontinuity of the distal fistula tract from the developing gut: direct histologic evidence for the mechanism of tracheoesophageal fistula formation.Anat Rec. 2002; 267: 220-224
- Esophageal atresia and tracheoesophageal malformations.in: Ashcraft K. Holder T. Pediatric surgery. Saunders, Philadelphia (Pa)1993: 249-269
- TTF-1 and HNF-3beta in the developing tracheoesophageal fistula: further evidence for the respiratory origin of the ‘distal esophagus’.J Pediatr Surg. 1999; 34: 1322-1326
- Patterning of the “distal esophagus” in esophageal atresia with tracheo-esophageal fistula: is thyroid transcription factor 1 a player?.J Surg Res. 2000; 92: 245-249
- Defective fibroblast growth factor signaling allows for nonbranching growth of the respiratory-derived fistula tract in esophageal atresia with tracheoesophageal fistula.J Pediatr Surg. 2000; 35: 1421-1425
- Growth factor signaling in lung morphogenetic centers: automaticity, stereotypy and symmetry.Respir Res. 2003; 4: 5
- Evidence from normal expression and targeted misexpression that bone morphogenetic protein (Bmp-4) plays a role in mouse embryonic lung morphogenesis.Development. 1996; 122: 1693-1702
- Bmp signaling regulates proximal-distal differentiation of endoderm in mouse lung development.Development. 1999; 26: 4005-4015
- TGF-beta signal transduction.Annu Rev Biochem. 1998; 67: 753-791
- Specificity, diversity, and regulation in TGF-beta superfamily signaling.FASEB J. 1999; 13: 2105-2124
- Fibroblast growth factor signaling in the developing tracheoesophageal fistula.J Pediatr Surg. 2003; 38: 474-477
- Aberrant fibroblast growth factor receptor 2 signalling in esophageal atresia with tracheoesophageal fistula.J Pediatr Surg. 2004; 39: 537-539
- Defective sonic hedgehog signaling in esophageal atresia with tracheoesophageal fistula.Surgery. 2003; 134: 345-350
- A role for sonic hedgehog signaling in the pathogenesis of human tracheoesophageal fistula.J Pediatr Surg. 2003; 38: 465-468
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© 2006 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
