Basic helix-loop-helix transcription factors and enteroendocrine cell differentiation

Abstract

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.

Fig. 1. Enteroendocrine cell differentiation from progenitors

Enteroendocrine cells arise from pluripotent stem cells that give rise to secretory progenitor cells that express the transcription factor, Math1. GFI1 expression drives differentiation to the goblet and Paneth cell lineages. Neurog3 represents the first specific step to initiate endocrine cell fate. Additional transcription factors, including Pax4 and Nkx2.2 are switched on as enteroendocrine cells mature. Once cells express NeuroD, they become restricted to an enteroendocrine cell fate before giving rise to various mature enteroendocrine cells.

Fig. 2. Differentiation and functional anatomy within the crypt-villus unit

Rapidly cycling crypt base columnar (CBC) and slowing cycling LRC+4 stem cells give rise to all four epithelial lineages. Enterocytes, goblet cells, and enteroendocrine cells differentiate as cells exit the lower crypt and a proliferative transit amplifying (TA) zone as they migrate up the crypt-villus axis. Some enteroendocrine cells differentiate just above the crypt base without without going through a TA population. In contrast, Paneth cells migrate to the crypt base and become intercalated between CBC stem cells.

Fig. 3. Functional cooperation between NeuroD and other proteins occupying the secretin gene enhancer

Four DNA binding proteins bind to a proximal enhancer in the secretin gene within 200 bp of the transcription start site. RREB1 binds directly to the enhancer and recruits CtBP and other proteins in multiprotein coactivator complex. Dotted lines indicate direct protein-protein interactions.