Defective fibroblast growth factor signaling allows for nonbranching growth of the respiratory-derived fistula tract in esophageal atresia with tracheoesophageal fistula

Background/Purpose: The fistula tract in esophageal atresia with tracheoeso phageal fistula (EA-TEF) appears to arise from a trifurcation of the embryo nic lung bud. Subsequently, it does not branch like the other bronchi, whic h also arise from the lung bud. Previous results have implied that aberrant mesenchymal-epithelial signaling in the developing foregut, possibly invol ving fibroblast growth factors, may allow for the nonbranching growth of th e fistula, and the ultimate development of the fistula tract in TEF. Methods: Adriamycin injections into pregnant rat darns induced EA-TEF forma tion in rat embryos. Control and Adriamycin-exposed embryos were harvested on the 13th gestational day, and the developing foregut was isolated with m icrodissection. mRNA was isolated from the developing fistula tract, embryo nic lung, and normal embryonic esophagus. Reverse transcription-polymerase chain reaction (RT-PCR) for the IIIb splice variant of the FGF2R receptor w as performed. Foregut specimens also were processed for histologic analysis , and immunofluorescence for FGF1 was performed. Results: FGF2R-IIIb is specifically absent from the developing fistula trac t in TEF, whereas it is present in the normal developing lung and esophagus . FGF1 also is uniquely absent from the developing fistula tract, but it is present in the normal lung mesenchyme. Conclusions: FGF1, FGF7, and FGF10 are critical mesenchymal factors that me diate proliferation and branching morphogenesis by the developing respirato ry epithelium. The absence of FGFZR-IIIb, the obligate common receptor for FGF7 and FGF10, from the fistula tract, and the absence of FGF1 in the fist ula tract mesenchyme, collectively imply the absence of a specific FGF sign aling pathway in the developing fistula tract. This absence of FGF signalin g could explain the lack of branching by the developing fistula tract as it grows caudally in the abnormally developing embryo. Downregulation of thes e components of the FGF signaling pathways may allow for a patterned compen sation by the embryo for the proximal foregut atresia in this anomaly. This compensation may then reestablish gastrointestinal continuity as the fistu la tract connects to the developing stomach. J Pediatr Surg 35:7421-1425. C opyright (C) 2000 by W.B. Saunders Company.