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The digestive system is essential for heterotrophic animals to acquire the energy needed for life. Although the digestive system has been diversified to adapt to the food environment during evolution, molecular mechanisms regulating the system’s organogenesis appear to be highly conserved among vertebrate species. The embryonic gut, which originates from the endoderm, lateral plate mesoderm, and neural crest cells, is first subdivided into the foregut, midgut, and hindgut and is then differentiated into various digestive organs, including the pharynx, esophagus, stomach, and small and large intestines, along the anterior-posterior axis of the embryo. In addition, the liver, pancreas, pharyngeal pouches, and respiratory organs are formed by projections from the foregut. Previous studies have shown that the embryonic gut is regionalized by transcription factors, such as Sox2, Pdx1, Cdx and Hox, which provide positional information along the anterior-posterior axis. Then, organ-specific morphogenesis and cytodifferentiation proceed in each organ. Recently, signaling pathways, including sonic hedgehog (Shh), Wnt, and Notch, have been shown to play important roles in the organogenesis of the gut. Noteworthy, during metamorphosis in the amphibian intestine, thyroid hormones reactivate such pathways and cause pre-existing epithelial cells to dedifferentiate into adult stem cells that generate the absorptive epithelium undergoing cell renewal similar to that in the mammalian intestine. Considering that this amphibian intestinal remodeling during metamorphosis mimics the mammalian intestinal maturation around the time of birth, thyroid hormone-regulated signaling pathways essential for stem cell development are suggested to be evolutionarily conserved among terrestrial vertebrates. Furthermore, in the adult intestine, such pathways are also involved in the regulation of stem cells to maintain epithelial cell renewal. We here review recent progress in this field, focusing on intestinal stem cells, and propose that clarification of molecular mechanisms underlying the development of the digestive system is interesting from the standpoint of evolutionary biology and also provides important information for the regenerative and cancer therapies of human digestive organs. (日本医科大学医学会雑誌 2015; 11: 155―160)

Molecular Mechanisms Underlying the Evolution and Development of the Digestive System