Patterning of the "distal esophagus" in esophageal atresia with tracheo-esophageal fistula: Is thyroid transcription factor 1 a player?

Background We have recently proposed that the "distal esophagus" in esophag eal atresia with tracheoesophageal fistula (EA/TEF) is actually embryologic ally derived from the middle branch of a trifurcation of the embryonic lung bud, which subsequently grows caudally in the foregut to connect with the developing stomach. We hypothesized that differential mRNA expression of th e lung-specific patterning transcription factor, thyroid transcription fact or 1 (TTF-1), in the developing fistula tract in TEF relative to the bronch i (the other branches of the lung bud trifurcation) might explain the uniqu e nonbranching pattern of growth of the fistula tract. Material and methods. EA/TEF was induced in Sprague-Dawley rat embryos via intraperitoneal injection of 2.2 mg/kg adriamycin into pregnant dams on Day s 6-9 of gestation. The foregut from embryos developing EA/TEF and from con trol embryos (no adriamycin) were isolated on Gestational Days 13.5, 15.5, and 17.5 (term = 21 days). Some were processed for whole-mount in situ hybr idization for TTF-1, while others were embedded and sectioned for histologi c analysis via in situ hybridization for TTF-1. Results. The expression of the respiratory-specific transcription factor TT F-1 is conserved in the epithelium of the developing fistula tract in TEF, The pattern of expression of TTF-1 in the fistula tract mirrors the express ion in the large airways of the developing lungs, despite the fact that the fistula tract does not form secondary branches to give rise to a lung. Conclusions. The fistula tract in TEF is a respiratory-derived structure th at expresses the lung-specific transcription factor TTF-1 throughout its de velopment in the foregut, Contrary to the patterning role that it normally plays in the developing lung, TTF-1 does not induce branching morphogenesis in the fistula tract. Thus, the nonbranching pattern of growth of the fist ula tract may be attributable to local mesenchymal-epithelial interactions that override TTF-1 patterning activity. (C) 2000 Academic Press.