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WIREs Dev Biol
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Compartmentalization of the foregut tube: developmental origins of the trachea and esophagus

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Abstract The mammalian trachea and esophagus share a common embryonic origin. They arise by compartmentalization of a single foregut tube, composed of foregut endoderm (FGE) and surrounding mesenchyme, around midgestation. Aberrant compartmentalization is thought to lead to relatively common human birth defects, such as esophageal atresia (EA) and tracheoesophageal fistula (EA/TEF), which can prevent or disrupt a newborn infant's ability to feed and breathe. Despite its relevance to human health, morphogenesis of the anterior foregut is still poorly understood. In this article, we provide a comprehensive review of trachea and esophagus formation from a common precursor, including the embryonic origin of the FGE, current models for foregut morphogenesis, relevant human birth defects, insights from rodent models, and the emerging picture of the mechanisms underlying normal and abnormal foregut compartmentalization. Recent research suggests that a number of intercellular signaling pathways and several intracellular effectors are essential for correct formation of the trachea and esophagus. Different types of defects in the formation of either ventral or dorsal foregut tissues can disrupt compartmentalization in rodent models. This implies that EA/TEF defects in humans may also arise by multiple mechanisms. Although our understanding of foregut compartmentalization is growing rapidly, it is still incomplete. Future research should focus on synthesizing detailed information gleaned from both human patients and rodent models to further our understanding of this enigmatic process. WIREs Dev Biol 2012, 1:184–202. doi: 10.1002/wdev.12 This article is categorized under: Vertebrate Organogenesis > From a Tubular Primordium: Non-Branched Birth Defects > Organ Anomalies

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Diagrammatic views of the normal anterior foregut. (a) Sideview of a midgestation embryo showing the anterior primitive foregut (fg) as a single tube with lung buds (green) emerging from the ventral foregut endoderm. (b) A ‘whole‐mount’ view of an isolated foregut just before compartmentalization. A transverse section through such a foregut at the level of the dashed line shows the surrounding mesenchyme and foregut endoderm. In the septation model, the lateral ridges will meet to divide the dorsal (pink) and ventral (green) foregut endoderm (fge) in to the esophagus and trachea, respectively. (c) Sideview of an adult showing the most anterior part of the foregut. The epiglottis provides the normal barrier between the trachea and esophagus, blocking the trachea during swallowing to prevent aspiration of food and liquid. (d) Front view of the isolated trachea and esophagus. The dashed line marks the location of the transverse section to the right, depicting the differentiated structures of each tube. Enlarged views at the far right show the different cellular arrangements of the developed epithelia.

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Models for how abnormal development of the notochord might influence foregut compartmentalization. In these diagrams, the following color code is used: gray, uncompartmentalized region of foregut endoderm (FGE); green, respiratory/vFGE; pink, digestive/dFGE; blue, neural tube (NT); dark purple, notochord (nt); orange lines, Hh signals emanating from notochord. (a) Normal foregut and notochord before (E10) and during (E11) foregut compartmentalization in the mouse. A transverse section shows the FGE, notochord, and neural tube at E10. (b) Improper resolution of the notochord from dorsal endoderm causes the notochord to remain tethered to the endoderm. As the foregut and notochord may grow rostrocaudally at different rates, tension between the notochord and foregut could distort the foregut to the point of causing discontinuity/atresia.14 (c) Improper resolution of the notochord causes large regions of Shh‐expressing notochord to be in close proximity to the foregut, potentially disrupting patterning and morphogenesis cues and leading to complete compartmentalization failure, as shown here, or EA/TEF (not shown).16,17,65,80 (d) Improper resolution of the notochord from endoderm causes cells that normally become dorsal foregut endoderm (dFGE) to remain associated with the resulting ‘notochord structure’, which then contains both notochord and dFGE cells. This leaves the dFGE with too few cells to form an esophagus upon septation.83

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Three‐dimensional representation of rodent model foregut compartmentalization defects. Green shading represents respiratory tract tubes, pink shading represents digestive tract tubes, and yellow shading represents tubes with mixed respiratory and digestive characteristics. (a) Normally compartmentalized foregut. (b) Foregut defect found in Nog null and Sox2 hypomorphic mutants, resembling Gross Type C esophageal atresia/tracheoesophageal fistula (EA/TEF) with a high distal fistula.64,65 (c) Defect found in Adriamycin‐treated, Nog−/−, and Gli2−/−, Gli3−/− animals. This phenotype resembles Gross Type C EA/TEF with a low distal fistula arising from the carina.55,64,66 (d) Defect found in Adriamycin‐treated animals; resembles Gross Type C EA/TEF with a fistula arising from the left main bronchus.55 (e) Defect found in Shh−/− and Foxf1a+/− mutants; the rostal foregut is improperly partitioned into the trachea and esophagus.67,68 In Shh−/− (*but perhaps not in Foxf1a+/−) mutants, the fistula arises from the level of the carina, merges with the left lobe of the lung forming a cyst‐like structure, and remerges to connect to the stomach. (f) Defect found in RAR mutants. There is no compartmentalization of the foregut, and the identity of the foregut tube is not known**; may resemble tracheal agenesis or Type 3 laryngotracheoesophageal (LTE) cleft.69 (g) Defect found in Nkx2‐1−/−, Ctnnb1 cKO (Foxg1tm1(cre)Skm; Ctnnb1tm2.1Kem/) conditional knock‐out (cKO), and Bmpr1a/b cKO (Shhtm1(EGFP/cre)Cjt;Bmpr1atm2.1Bhr/tm2.2Bhr; Bmpr1btm1Kml). There is no compartmentalization of the foregut, which has lost all/most respiratory specification (essentially tracheal agenesis) and varying degrees of abnormal lung development.67,70 (h) Defect found in Bmp4 ventral foregut cKO mutants (Shhtm1(EGFP/cre)Cjt; Bmp4tm3.1Blh/tm2Blh); resembles tracheal agenesis.67,71 (i) Defect found in Atmin−/− mutants; resembles tracheal agenesis with low degree of lung development.72 (j) Defect found in Wnt2/2b double‐knockout mutants and Ctnnb1 cKO (Shhtm1(EGFP/cre)Cjt; Ctnnb1tm2.1Kem); resembles tracheal agenesis with no lung development.73,74

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The spectrum of human foregut compartmentalization anomalies. (Top) Three‐dimensional representations of Gross Types A–D morphological classifications of esophageal atresia (EA), as evidenced by an upper esophageal pouch, with or without fistula. Type A: isolated EA. Type B: EA with proximal tracheoesophageal fistula (TEF). Type C: EA with distal TEF. Type D: EA with proximal and distal TEF.32 *Percent incidence among cases of EA/TEF (including H‐type isolated fistula).35 (Middle) Laryngotracheoesophageal (LTE) clefts are relatively rare malformations that involve large continuous regions of communication between the larynx or trachea and esophagus.29 The extent of the communication in each type is illustrated by brackets. **Percent incidence among cases of LTE clefts.29 (Bottom left–bottom right) Tracheal agenesis involves the absence of a trachea where lungs sometimes arise from the esophagus;30 Esophageal stenosis (narrowing) occurs both on its own (two‐third of cases) and in combination with EA;31 Isolated (H‐type) TEF;35 Bronchoesophageal fistula is rare and usually occurs with EA.33

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Early development of the anterior definitive endoderm and notochord. (a) Precursors of the anterior definitive endoderm (bracket) reside in the posterior epiblast (blue) at prestreak (PS) stages, just before gastrulation. (b) After passing through the anterior primitive streak (yellow and red stripes) at the early streak (ES) stage, foregut endoderm precursors migrate anteriorly, displacing visceral endoderm (orange) by intercalation.12 (c) At mid‐streak (MS) stage, the ventral foregut endoderm (vFGE) precursors precede those of the dorsal foregut endoderm (dFGE). (d) By the late streak (LS) stage, the node (purple), the origin of trunk notochord, is forming just posterior to the dFGE precursors. (e) At early headfold (EHF) stage, the vFGE precursors are at the most anterior region of the embryo and cells from the node have become embedded within the dFGE at the midline as presumptive notochord (nt), seen in cross section in panel (h). (f) By early somite stages the FGE precursors (arrow, vFGE; arrowhead, dFGE) are all rostral to the anterior intestinal portal (AIP), and the notochord is resolving from the dFGE [cross‐section panel (i)]. (g) At E9.5, the gut tube is fully closed [asterisk (*) represents future site of lung bud formation], and the notochord is completely resolved from the endoderm. (h–k) Cross sections of embryos shown above to depict foregut and notochord morphology (information compiled from Ref2–8,13).

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Three models for foregut compartmentalization. At E10 in the mouse, the anterior foregut endoderm is a single tube with nascent ventral lung buds at the level of dashed line ‘A, B, and C’. The ‘outgrowth’ model (top) states that the trachea grows rapidly out of the single foregut tube following the lung buds; dashed line (the original level of the lung buds) ‘A’ stays at the level of tracheal/esophageal divergence.18,19 The ‘watershed’ model (middle) suggests that both the esophagus and trachea elongate and separation is maintained by mesenchyme just caudal to the point of divergence; dashed line ‘B’ remains at the level of tracheal/esophageal divergence.20 In the ‘septation’ model (bottom) the lateral ridges (Figure 3) form a septum that travels up the foregut, dividing the ventral and dorsal domains into the trachea and esophagus, respectively; dashed line ‘C’ remains a the level of the main bronchi.21,22 By E12, when compartmentalization is largely complete, the original location of the lung buds (dashed lines A, B, and C) is at the caudal larynx in the case of the ‘outgrowth’ or ‘watershed’ model but at the level of the main bronchi in the case of ‘septation’. Pink, esophagus/alimentary; green, trachea/respiratory.

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Fate map of the anterior foregut endoderm from early headfold to midsomite stages. This figure summarizes findings from experiments in which anterior definitive endoderm (ADE) cells were fate mapped at the early headfold (EHF) stage and assessed after 24 h of culture.5,8,9 The color code shows where the descendents are found at E8.5 for a given domain of EHF endoderm cells. Cells at the midline of the EHF embryo (M1–M3) end up at the midline of the foregut tube. M1 becomes largely medial ventral foregut endoderm (vFGE), M2 contributes to the terminus of the anterior FGE, and M3 becomes medial dorsal foregut endoderm (dFGE). L1–L3 domains contribute mostly to regions just lateral to their medial counterparts.

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