Scientists have found that a single gene plays an essential role in controlling normal intestinal development. In utero, the gastrointestinal (GI) tract develops from the foregut, which becomes the esophagus, stomach, and upper part of the small intestine; the midgut, which gives rise to the small intestine; and the hindgut, which forms the cecum and colon. The formation of the intestine is directed by a complex network of precisely timed signals passing between and within cells of these developing tissues, including layers of cells that will form the lining of the intestine (epithelial cells) and cells that will form intestinal smooth muscle and other intestinal tissues (mesenchymal cells). Some of these signals are so essential for life that, when mutated, the resulting deficiency causes death in utero. For example, mutation of a mouse gene important to intestinal development, called Cdx2, is lethal for mice at the embryonic stage. Humans also carry a form of this gene, referred to as CDX2.
To investigate the role that the Cdx2 gene plays specifically in development of the intestine, scientists created a mouse model in which the Cdx2 gene is only mutated in developing intestinal cells; with this restricted Cdx2 deficiency, the developing mice do not die in utero and can thus be studied. When the scientists compared this mutant mouse model with normal mice, they observed some dramatic and surprising changes in the development of the intestine. For example, the colon in the mutant mouse failed to develop correctly, mimicking a disorder in humans known as colonic atresia. Also, epithelial cells on the inner layer of the intestine did not differentiate to form the correct cell types and structures, such as villi with brush border membranes needed for nutrient absorption. Instead, the mutant epithelial cells more closely resembled cell types found in the upper GI tract, specifically the esophagus, rather than those found in a normal intestine. Analyses of the “transcriptome”—the collection of genes turned on (expressed)—in the small intestine confirmed that the Cdx2-deficient small intestine had converted to a more esophageal type by turning on genes typically seen in the esophagus but not the intestine. As the intestine develops, Cdx2 production normally becomes restricted to epithelial cells. However, the researchers showed that cells of the other tissue layers within the intestine were also altered to be more esophagus-like, suggesting that Cdx2 deficiency-related epithelial modifications subsequently caused changes in adjacent tissue layers, converting them to an esophageal program as well.
These experiments demonstrate the importance of Cdx2 to proper intestinal development by characterizing the repercussions of its removal, including abnormal colon formation and a switch to an upper GI tract phenotype. Based on these findings, Cdx2 is now recognized as playing a critical role in programming tissues along the length of the GI tract to have specific cell types and features to suit their different functional needs. Beyond informing our understanding of intestinal development, these studies have implications for human conditions in which intestinal programming is altered, such as colonic atresia.
Gao N, White P, and Kaestner K: Establishment of intestinal integrity and epithelial-mesenchymal signaling by Cdx 2. Dev Cell 16: 588-599, 2009.
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