Sonic hedgehog expression correlates with fundic gland differentiation in the adult gastrointestinal tract. (Stomach).

Background: Sonic hedgehog (Shh) is an important endodermal morphogenetic signal during the development of the vertebrate gut. It controls gastrointestinal patterning in general, and gastric gland formation in particular. We have previously shown that Shh regulates gastric gland proliferation in the adult but detailed analysis of its expression along the adult gastrointestinal tract has never been undertaken. We therefore studied Shh expression along the normal human and rodent adult gastrointestinal tract as well as in intestinal metaplasia of the stomach, gastric and intestinal metaplasia of the oesophagus, and gastric heterotopia in Meckel's diverticulum.

Methods: The studies were performed with in situ hybridisation and by immunohistochemistry using an antibody that recognises the Shh precursor form.

Results: We found that in the normal gastrointestinal tract, high levels of Shh were expressed in the fundic glands of the stomach. Shh expression was also found in fundic gland metaplasia and heterotopia. However, Shh expression was lost in intestinal metaplasia of the stomach.

Conclusion: We found a strong correlation between Shh expression and fundic gland differentiation. Our current study therefore provides evidence that in addition to its role in gastric epithelial development, Shh plays a unique role in gastric epithelial differentiation in adults.

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During organogenesis, the cells of the endodermal layer give rise to the liver, pancreas, and epithelial cells of the lung and gastrointestinal tract. Differentiation of these different organs with their respective functional cell types occurs through complex mesenchymal-endodermal interaction. In this interaction, the hedgehog (Hh), fibroblast growth factor, Wnt, and transforming growth factor [beta] families of secreted proteins play a key role. (1)

Hh was initially identified in a genetic screen for segment polarity genes in Drosophila. (2) In vertebrates, three hedgehog genes have been identified, sonic hedgehog (Shh), Indian hedgehog, and desert hedgehog. All three Hhs bind to the same receptor (patched) which controls the activity of a second receptor (smoothened). (3) Both Shh and Indian hedgehog play a role in endodermal/ectodermal-mesodermal interactions in the gut. (4-14)

Expression of Shh in the gastrointestinal tract has been described during development in many vertebrate systems, including the mouse, (4) chick, (5) human, (13) and frog. (14) In all species examined, Shh is expressed from the earliest time points of gastrointestinal development, restricted in its expression to the endoderm. The murine gut has been widely examined for Shh mRNA expression throughout development. At a late stage of development, 18.5 days post coitus, one day prior to birth, Shh mRNA is detected in the glandular epithelium of the stomach, small intestine, and colon. (9) However, although this is a late stage of intrauterine development, the murine gastrointestinal tract undergoes major morphological and functional changes during the first three postnatal weeks, including formation of intestinal crypts and maturation of the gastric glands." (15 16) It is therefore difficult to infer from these data what happens to Shh mRNA expression in the adult.

Several studies have addressed the functional role of Shh expression in the developing gut. Studies in chick and mouse using either overexpression or inactivation of Shh suggest that during development, Shh is a critical endodermal signal in the epithelial-mesodermal signalling involved in specification of differentiation along the anterior-posterior as well as the radial axis of the vertebrate gut. (5-14) Shh null mice display gastrointestinal malformations, including failure of the trachea and oesophagus to separate normally, (7) gut malrotation, and small intestinal and anus atresias. (9) The gastric epithelium of Shh null mice shows epithelial hyperplasia and alkaline phosphatase expression, a sign of intestinal differentiation. (9) The critical role of Shh in gastric epithelial development is further supported by the finding that the Hh inhibitor cyclopamine causes pancreatic transformation of the stomach in embryonic chicks. (10)

The lack of information on Hh expression in the adult is unfortunate as these proteins are likely to play an important role in the orchestration of the complex patterns of epithelial proliferation and differentiation in this rapidly regenerating system. Since Shh is an important polarising …