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Division of Gastroenterology, GRASP Digestive Disease Center, Tufts-New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111
Address all correspondence and requests for reprints to: Andrew B. Leiter M.D., Ph.D., Division of Gastroenterology No. 218, New England Medical Center, 750 Washington Street, Boston, Massachusetts 02111. E-mail: aleiter{at}tufts-nemc.org.
Abstract
For over 30 yr, it has been known that enteroendocrine cells derive from common precursor cells in the intestinal crypts. Until recently, relatively little was understood about the events that result in commitment to endocrine differentiation or the segregation of over 10 different hormone-expressing cell types in the gastrointestinal tract. The earliest cell fate decisions appear to be regulated by the Notch signaling pathway. Notch is inactive in endocrine precursor cells, allowing for expression of the proendocrine basic helix-loop-helix proteins Math1 and neurogenin3. Differentiating precursor cells activate Notch in neighboring cells to switch off expression of proendocrine factors and inhibit endocrine differentiation. Math1 is the first factor involved in endocrine specification, committing cells to become one of three secretory lineages—goblet, Paneth, and enteroendocrine. Neurogenin3 appears to be a downstream target that is essential for endocrine cell differentiation. Events that control the segregation of each mature lineage from progenitor cells have not been characterized in detail. The transcription factors Pax4, Pax6, BETA2/NeuroD, and pancreatic-duodenal homeobox 1 have all been implicated in enteroendocrine differentiation. BETA2/NeuroD appears to coordinate secretin gene expression in S-type enteroendocrine cells with cell cycle arrest as cells terminally differentiate. Powerful genetic approaches have established the murine intestine as the most important model for studying enteroendocrine differentiation. Enteroendocrine cells in the mouse are remarkably similar to those in humans, making it likely that insights learned from the mouse may contribute to both our understanding and treatment of a variety of human disorders.
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