Abstract
Mesenchymal cells underlying the definitive endoderm in vertebrate animals play a vital role in digestive and respiratory organogenesis. Although several signaling pathways are implicated in foregut patterning and morphogenesis, and despite the clinical importance of congenital tracheal and esophageal malformations in humans, understanding of molecular mechanisms that allow a single tube to separate correctly into the trachea and esophagus is incomplete. The homoebox gene Barx1 is highly expressed in prospective stomach mesenchyme and required to specify this organ. We observed lower Barx1 expression extending contiguously from the proximal stomach domain, along the dorsal anterior foregut mesenchyme and in mesenchymal cells between the nascent esophagus and trachea. This expression pattern exactly mirrors the decline in Wnt signaling activity in late development of the adjacent dorsal foregut endoderm and medial mainstem bronchi. The hypopharynx in Barx1−/− mouse embryos is abnormally elongated and the point of esophago-tracheal separation shows marked caudal displacement, resulting in a common foregut tube that is similar to human congenital tracheo-esophageal fistula and explains neonatal lethality. Moreover, the Barx1−/− esophagus displays molecular and cytologic features of respiratory endoderm, phenocopying abnormalities observed in mouse embryos with activated ß-catenin. The zone of canonical Wnt signaling is abnormally prolonged and expanded in the proximal Barx1−/− foregut. Thus, as in the developing stomach, but distinct from the spleen, Barx1 control of thoracic foregut specification and tracheo-esophageal septation is tightly associated with down-regulation of adjacent Wnt pathway activity.
Highlights
The primitive gut develops from the union of definitive endoderm with the splanchnic mesoderm, first appearing as a fold on the ventral surface of unturned mouse embryos
Various secreted signals, including Sonic hedgehog (Shh), Fibroblast growth factor (FGF) 10 and FGF receptor 2, Bone morphogenetic protein (BMP)-4 and Noggin, and Wnts are implicated in foregut patterning because disruption of the corresponding genes leads to foregut development defects, including the EA/TEF complex [4]
Dynamic Barx1 expression in foregut mesenchyme Because Barx1 expression is especially prominent in the stomach, which is severely malformed in Barx12/2 mice [3], we initially assumed that the esophageal defects were secondary [10], they were not readily explained on that basis
Summary
The primitive gut develops from the union of definitive endoderm with the splanchnic mesoderm, first appearing as a fold on the ventral surface of unturned mouse embryos. By the end of embryonic day (E) 8, the anterior gut tube forms the foregut diverticulum, which originates from a small groove in the ventral midline endoderm and will differentiate into most of the oral cavity, pharynx, esophagus, and respiratory tract. Between E9 and E9.5, the anterior foregut narrows to form the prospective esophagus, coinciding with appearance on the ventral aspect of the oropharyngeal floor of the laryngo-tracheal groove, which extends to form the trachea [1,2]. Tracheo-esophageal fistula and esophageal atresia (EA/ TEF), congenital defects that occur in 1 per 2,000 to 4,000 live human births, often in association with other digestive tract anomalies [6], reflect errors in patterning and morphogenesis of the anterior (thoracic) foregut tube. Combined loss of Wnt and Wnt2b or inactivation of ß-catenin (Ctnnb1) in the endoderm lead to failure in foregut separation, whereas activation of ß-catenin in the endoderm expands the respiratory domain in the dorsal foregut endoderm [7,8]
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