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Basic helix-loop-helix transcription factors
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Diabetes, Obesity and Metabolism 13 (Suppl. 1): 5–12, 2011.
? 2011 Blackwell Publishing Ltdreview article
Basic helix-loop-helix transcription factors
and enteroendocrine cell differentiation
H. J. Li, S. K. Ray, N. K. Singh, B. Johnston A. B. Leiter
Division of Gastroenterology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
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.
Keywords: basic helix-loop-helix proteins, enteroendocrine cells, intestinal stem cells, MATH1, neuroD1, neurogenin3
Date submitted 1 April 2011; date of final acceptance 13 May 2011
Introduction
The mammalian gastrointestinal tract contains the largest
population of hor
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