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WIREs Dev Biol
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The initial establishment and epithelial morphogenesis of the esophagus: a new model of tracheal–esophageal separation and transition of simple columnar into stratified squamous epithelium in the developing esophagus

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The esophagus and trachea are tubular organs that initially share a single common lumen in the anterior foregut. Several models have been proposed to explain how this single‐lumen developmental intermediate generates two tubular organs. However, new evidence suggests that these models are not comprehensive. I will first briefly review these models and then propose a novel ‘splitting and extension’ model based on our in vitro modeling of the foregut separation process. Signaling molecules (e.g., SHHs, WNTs, BMPs) and transcription factors (e.g., NKX2.1 and SOX2) are critical for the separation of the foregut. Intriguingly, some of these molecules continue to play essential roles during the transition of simple columnar into stratified squamous epithelium in the developing esophagus, and they are also closely involved in epithelial maintenance in the adults. Alterations in the levels of these molecules have been associated with the initiation and progression of several esophageal diseases and cancer in adults. WIREs Dev Biol 2015, 4:419–430. doi: 10.1002/wdev.179 This article is categorized under: Signaling Pathways > Cell Fate Signaling Vertebrate Organogenesis > From a Tubular Primordium: Non-Branched Birth Defects > Organ Anomalies
Old and new models of tracheal–esophageal separation. (a) Schematic presentation of three old models of foregut separation: (1) The outgrowth model in which the trachea extends from the common foregut tube as the lung buds grow, while the common foregut tube becomes the esophagus. The arrows indicate the extension of the trachea and esophagus; (2) the watershed model in which both the trachea and esophagus elongate while separated by a mesenchymal septum that serves as a wedge to prevent the extension of the lateral wall at the dorsal–ventral midline. The empty arrowhead indicates hypothetical mesenchymal condensation which has yet to be identified. According to this model, increased proliferation is expected to occur at the ventral and dorsal sides as compared to the midline lateral wall (the dotted rectangle region) of the common foregut; and (3) the septation model in which the epithelial cells at the dorsal–ventral midline make contact across the lumen and fuse to form a septum. The arrowhead indicates the septum. (b) The new model, the ‘splitting and extension model’, proposes that the separation of the trachea and esophagus initiates at the level where the lung grows out and moves rostrally. A saddle‐like structure (red arc) moves up and splits the anterior foregut. Meanwhile, the nascent trachea and esophagus extend their lengths as indicated by arrows. This model is based on live‐imaging of the cultured anterior foregut which was isolated from E9.5 Sox2‐EGFP embryos. (c) Snapshots of the foregut culture that was maintained for 96 h. Note the bottom‐up splitting of the foregut and extension of the trachea and esophagus. Also note that the fluorescent intensity of GFP is stronger in the esophagus and stomach than the trachea and lung. See Movie S1 for details. Asterisk indicates the epithelial saddle. Arrowheads indicate lung buds. Abbreviations: Ve, ventral; Do, dorsal; Pr, proximal (rostral); Di, distal (caudal); CF, common foregut; Lu, lung; St, stomach; Es, esophagus; Tr, trachea.
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Deletion of p63 blocks the conversion of simple columnar to stratified squamous epithelium in the developing esophagus. The epithelium remains simple columnar and ciliated, and it produces glycoproteins (Alcian blue positive as indicated by the arrowheads) Scale bar: 50 µm.
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Conversion of simple columnar to stratified squamous epithelium in the developing esophagus. (a) The epithelium in the nascent esophagus is simple columnar and expresses SOX2, P63, K8, and K18. The epithelial stratification starts with the reduction of K8 and K18 and gain of K5 and K14 in the basal layer. Activation of BMP signaling as reported by the BRE‐lacZ allele is required for the squamous differentiation of top layers of the epithelium. (b) Ciliated cells detected by a‐tubulin labeling, distribute at intervals in the E18.5 esophagus. Ciliated cells can be detected from E13.5 to p3. Arrowheads indicate ciliated cells (light green). Abbreviation: epi, epithelium; mes, mesenchyme. Scale bar: 50 µm.
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Histology of the adult mouse esophagus. The stratified squamous epithelium consists of undifferentiated basal and differentiated suprabasal cells. Note that the epithelium is covered with a layer of keratin, which is not present in the human esophagus. The mesenchyme is composed of multiple layers of muscles (muscularis mucosa and muscularis externa which can be further divided into inner circular and outer longitudinal muscles). The esophagus is wrapped by the tunica adventitia, a layer of loose fibrous tissue. The arrowhead indicates a blood vessel. Abbreviation: IC, inner circular; OL, outer longitudinal. Scale bar: 50 µm.
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Constriction site in the upper common foregut tube and its implication in the formation of EA/TEF. (a–c) The front, back and side views of the E9.5 (25 somite stage) foregut stained with E‐cadherin antibody to visualize the epithelium. The double arrows indicate the constriction site (a short segment). (d) 3‐D reconstruction of the epithelial tube of the E9.5 foregut stained with E‐cadherin. Note the constriction site at the upper half of the tube (arrows). (e) EA/TEF formation model: Two waves of bottom‐up movement of the epithelial saddle during the formation of EA/TEF in genetic mutants (e.g., Nog−/−). The first wave of movement stops at the constriction site (double arrows) and leads to the formation of TEF. The second wave starts right above the constriction site and leads to the formation of EA. (f) The most common EA/TEF is proximal EA with distal TEF as illustrated in some Nog−/− mutants (example 1). TEF can be detached from the trachea and becomes the isolated TEF. Similarly, EA/TEF can be linked to the trachea with a common tube, leading to the formation of H‐shape EA/TEF as seen in a limited number of Nog−/− mutants (example 2).
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Dorsal–ventral patterning of signaling molecules and transcription factors during the separation of the trachea and esophagus. (a) Schematic diagram of molecules located in the epithelium and mesenchyme of the E9.5 anterior foregut. Note that BARX1 is enriched in the mesenchyme of the tracheoesophageal groove. * The expression pattern of ASCIZ (ATM substrate Chk2‐interacting Zn2+‐finger protein) remains to be determined. # Trachea‐esophageal separation seems normal in the available p63 deletion mutants. (b) Expression of the transcription factors SOX2 and P63 during the separation of the early foregut. Note that P63 is expressed in some of the epithelial cells in the ventral side of the foregut prior to separation (arrowheads). Abbreviation: e, epithelium; m, mesenchyme; Tr, trachea; Es, esophagus. Scale bar: 50 µm.
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Signaling Pathways > Cell Fate Signaling
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Vertebrate Organogenesis > From a Tubular Primordium: Non-Branched