One shall become two: Separation of the esophagus and trachea from the common foregut tube

Abstract

The alimentary and respiratory organ systems arise from a common endodermal origin, the anterior foregut tube. Formation of the esophagus from the dorsal region and the trachea from the ventral region of the foregut primordium occurs via a poorly understood compartmentalization process. Disruption of this process can result in severe birth defects, such as esophageal atresia and tracheoesphageal fistula (EA/TEF), in which the lumina of the trachea and esophagus remain connected. Here we summarize the signaling networks known to be necessary for regulating dorso-ventral patterning within the common foregut tube and cellular behaviors that may occur during normal foregut compartmentalization. We propose that dorso-ventral patterning serves to establish a lateral region of the foregut tube that is capable of undergoing specialized cellular rearrangements, culminating in compartmentalization. We review established as well as new rodent models that may be useful in addressing this hypothesis. Finally, we discuss new experimental models that could help elucidate the mechanism behind foregut compartmentalization. An integrated approach to future foregut morphogenesis research will allow for a better understanding of this complex process.

Paediatric Tracheomalacia

“…6 Improper foregut separation of the trachea from the oesophagus results in congenital abnormalities such as laryngotracheoesophageal clefts, tracheo-oesophageal fistulae (TOF), and esophageal atresia (EA) that are associated with tracheomalacia. 5,6 In addition to the separation from the oesophagus, the airway must develop from a single lumen into the more than 10 20 conducting airways found in the mature lung. The trachea and main bronchi form during the fourth week of gestation.…”

“…By the third week of gestation, the endoderm develops into the foregut. 5 An outpouching of the foregut develops during the fourth week of gestation and will give rise to all of the conducting airways. The trachea develops from the more proximal ventral foregut endoderm while the oesophagus arises Page 5 of 23 A c c e p t e d M a n u s c r i p t from the dorsal foregut endoderm.…”

The microscopic anatomy of the esophagus including the individual layers, specialized tissues, and unique components and their responses to injury

“…Similarly, downregulation of Sox2 in the early foregut leads to EA/TEF . The functions of Sox2 and Nkx2.1 are regulated by several signaling pathways . WNT/β‐catenin signaling pathway plays a crucial role in specifying Nkx2.1 + respiratory endoderm progenitors during development.…”

Interkinetic nuclear migration in the tracheal and esophageal epithelia of the mouse embryo: Possible implications for tracheo‐esophageal anomalies

“…According to the "splitting and extension" model, the separation of the trachea and esophagus is initiated at the level where the lung grows outward and moves rostrally; a saddle-like structure at the separation site moves up and splits the anterior foregut. The previous reports indicate that neither a localized increase in cell proliferation nor apoptosis plays an active role in these processes (Yu et al 2005;Ioannides et al 2010;Billmyre et al 2015). Transcription factors and signaling molecules that are involved in the dorsal-ventral patterning of the anterior foregut and proper separation of the esophagus from the respiratory system as well as those involved in development of the esophageal epithelium and mesenchyme have been well documented (for review see Jacobs et al 2012;Billmyre et al 2015;Zhang et al 2016).…”