Boundaries, junctions and transitions in the gastrointestinal tract

Abstract

Contiguous regions along the mammalian gastrointestinal tract, from the esophagus to the rectum, serve distinct digestive functions. Some organs, such as the esophagus and glandular stomach or the small bowel and colon, are separated by sharp boundaries. The duodenal, jejunal and ileal segments of the small intestine, by contrast, have imprecise borders. Because human esophageal and gastric cancers frequently arise in a background of tissue metaplasia and some intestinal disorders are confined to discrete regions, it is useful to appreciate the molecular and cellular basis of boundary formation and preservation. Here we review the anatomy and determinants of boundaries and transitions in the alimentary canal with respect to tissue morphology, gene expression, and, especially, transcriptional control of epithelial identity. We discuss the evidence for established and candidate molecular mechanisms of boundary formation, including the solitary and combinatorial actions of tissue-restricted transcription factors. Although the understanding remains sparse, genetic studies in mice do provide insights into dominant mechanisms and point the way for future investigation.

Figure 1. Organization of regions in the gastrointestinal tract

Left: The foregut, midgut and hindgut are classically defined according to the blood supply, as indicated. Right: Colors in the diagram refer to distinctive epithelia within the alimentary canal. In mice, the stratified squamous epithelium of the esophagus (crimson) extends into the dome-like forestomach, before forming a sharp, single-cell boundary with the glandular columnar epithelium of the gastric corpus (dark brown). As discussed in the text, the boundary between the gastric body and antral-pyloric epithelia (light brown) is less distinct, while that between the stomach and small intestine (green), marked by the pyloric sphincter, is sharp. Small intestine regions have different digestive functions and characteristic patterns of genes expression, without well-defined boundaries. The villous epithelium of small intestine transitions abruptly into a flat, non-villous epithelium at the ileo-cecal valve, which is followed by a specialized cecum (yellow) and the remainder of the colon (orange).

Figure 2. Expression domains of transcription factors that participate in digestive tissue identity and boundary formation

Left: Schematic diagram of the alimentary canal, stretched in the rostro-caudal axis, with discrete regions represented in the same colors as in Figure 1. Center: Expression domains of factors with known functions in epithelial specification or boundary formation. Factors expressed in the mesenchyme and epithelium are represented in black and gray, respectively. The many Hox-cluster genes expressed in the gut are not represented; see [39, 42, 48] for Hox gene expression. Right: Histologic demonstration of sharp anatomic boundaries at the mouse foregut squamo-columnar junction (top, H&E stain (adult)), gastroduodenal boundary (middle, H&E stain (adult), CDX2 immunohistochemistry (E16)), and ileo-cecal valve (bottom, Periodic acid Schiff stain (adult)). Arrows point to the respective junctions. At the foregut squamo-columnar junction, note the eosinophilic keratin lining the squamous epithelium, above the arrow, and its absence over glandular epithelium below the arrow.

Figure 3. Illustrative boundary defects in mutant mice

(A-D) Hematoxylin and eosin (H&E)-stained neonatal stomach tissues from wild-type (A) and Barx1^-/- (B) mice [52]. The homeotic posteriorization in Barx1^-/- stomach is evident from ectopic presence of intestinal villi (B) and expression of the intestinal marker CDX2 (D) as early as E12.5 [27]. (E, F) H&E-stained wild-type (E) and Pdx1^-/- (F) tissues at E18.5 reveal defective pylorus development in Pdx1^-/- mice. Normally the stomach (s) opens into the duodenum (d) at the pylorus (p), where well-defined Brunner’s glands (b) are found. In Pdx1^-/- mutants, a cavity that lacks villi and is lined by a cuboidal epithelium forms in this region [23].