For over 30 years it has been known that enteroendocrine cells derive from common precursor cells in the intestinal crypts. Until recently little was understood about the events that result in commitment to endocrine differentiation or the eventual segregation of over 10 different hormone-expressing cell types in the gastrointestinal tract. Enteroendocrine cells arise from pluripotent intestinal stem cells. Differentiation of enteroendocrine cells is controlled by the sequential expression of three basic helix-loop-helix transcription factors, Math1, Neurogenin 3 (Neurog3) and NeuroD. Math1 expression is required for specification and segregation of the intestinal secretory lineage (Paneth, goblet,and enteroendocrine cells) from the absorptive enterocyte lineage. Neurog3 expression represents the earliest stage of enteroendocrine differentiation and in its absence enteroendocrine cells fail to develop. Subsequent expression of NeuroD appears to represent a later stage of differentiation for maturing enteroendocrine cells. Enteroendocrine cell fate is inhibited by the Notch signalling pathway, which appears to inhibit both Math1 and Neurog3. Understanding enteroendocrine cell differentiation will become increasingly important for identifying potential future targets for common diseases such as diabetes and obesity.
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