Dorsoventral patterning in oesophageal atresia with tracheo-oesophageal fistula: Evidence from a new mouse model

Abstract

Background/purpose: The well-established Adriamycin rat model of oesophageal atresia (OA) and tracheo-oesophageal fistula (TOF) complements recently described mouse genetic models in which loss of function mutations in foregut patterning genes, such as Nkx2.1 (Ttf 1), lead to OA/TOF. The authors aimed to integrate the 2 systems by adapting the Adriamycin model to the mouse to study molecular aspects of tracheo-oesophageal development.

Methods: Pregnant CBA/Ca mice were injected intraperitoneally with 4 mg/kg of Adriamycin on embryonic days 7.5 and 8.5. Embryos and fetuses of various gestational ages were subjected to morphologic or histologic examination. Sections were stained with H & E or processed for immunohistochemistry using an antibody specific for Nkx2.1.

Results: Tracheo-oesophageal malformations were observed in 47% of Adriamycin-treated embryos. Early foregut development was similar in Adriamycin-exposed and control embryos but, by E11.5, many treated embryos had an undivided oesophago-trachea, which gave rise to the lung buds and a fistula to the stomach. The fistula originated from the dorsal aspect of the undivided tube and was negative for Nkx2.1, or showed only transient Nkx2.1 expression, compared to the strongly positive bronchi ventrally.

Conclusions: The Adriamycin model of OA is adaptable to the mouse. In the absence of tracheo-oesophageal separation, the dorsal fistula retains its nonrespiratory commitment suggesting that dorsoventral patterning of foregut development is undisturbed by Adriamycin exposure.