Role of Sonic hedgehog in the development of the trachea and oesophagus

Background/purpose: The secreted glycoprotein, Sonic hedgehog (Shh) plays an important patterning role in the development of many organ systems. The authors aimed to study the temporal and spatial pattern of expression of Shh and its receptor Ptc1 during the development of the anterior foregut and to test the hypothesis that the Shh expression pattern is disturbed during the development of oesophageal atresia (OA) and tracheo-oesophageal fistula (TOF) in Adriamycin-treated mouse embryos.

Methods: Saline and Adriamycin-treated (4 mg/kg) CBA/Ca embryos were harvested between embryonic days (E) 10.5 and 12.5, and Shh and Ptc1 expression was studied by whole-mount and section in situ hybridisation using digoxygenin-labelled riboprobes.

Results: At E10.5, saline-treated embryos had an undivided foregut in which the ventrally placed prospective tracheal epithelium was positive for Shh, whereas the dorsal part was negative. At E11.5, this pattern had reversed with the separated trachea becoming negative and the oesophagus gaining expression of Shh. Ptc1 was expressed in the mesoderm adjacent to Shh expressing endoderm at both stages. Affected Adriamycin-treated embryos had an undivided foregut at E11.5, the epithelium of which showed diffuse Shh staining that lacked the dorso-ventral patterning seen in controls.

Conclusions: The reversal in the dorso-ventral pattern of Shh expression during the narrow embryologic window in which tracheo-oesophageal separation is initiated suggests that Shh may play an important role in this process. Transient disturbance of this pattern may underlie the abnormal organogenesis in the Adriamycin model.