Review
Gut endocrine cell development

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Introduction

Endocrine cells are scattered throughout the gastrointestinal mucosa from the stomach to the colon and constitute one of the largest endocrine systems in the body. Enteroendocrine cells labeled by chromogranin A comprise about 1% of all epithelial cells in the gastrointestinal tract and are surrounded by mucus, chief, and parietal cells in the stomach, and enterocyte, goblet and Paneth cells in the intestine (Fig. 1). The enteroendocrine system consists of at least 15 different cell types that can be classified based on their main hormonal products and on the ultrastructure of their secretory granules (Rindi et al., 2004). A given enteroendocrine cell secretes one or more hormone or hormone-like substance, which is released directly into the lamina propria and diffuses into the capillaries. These hormones include gastrin, histamine, serotonin, cholecystokinin (CCK), somatostatin and glucagon-like peptides (GLP1 and GLP2) (Rindi et al., 2004). Although enteroendocrine cells are very scarce, they are essential regulators of digestion, gut motility, appetite, and metabolism.

The development of enteroendocrine cells is a fascinating biological problem: how is the relative proportion of the individual subtypes maintained? How are so many different cell types specified from a common precursor? And how is the endocrine compartment maintained in the gastrointestinal epithelium with its rapid and life-long turnover? However, the study of the mechanisms of enteroendocrine cell differentiation is not only an “academic exercise” but of relevance to human health and disease on multiple levels. First, deficiencies in enteroendocrine cell specification or survival contribute to human diseases, as exemplified by congenital malabsorptive diarrhea, discussed in detail below, which is due solely to deficient enteroendocrine cells. Second, several enteroendocrine cells play a role in the control of glucose homeostasis and thus diabetes, and there relatedness to pancreatic beta-cells makes transdifferentiation of enteroendocrine cells an interesting possibility. Therefore, lessons learned from the study of normal gut endocrine cell development promise to guide treatments for metabolic diseases.

Section snippets

Embryonic origin of enteroendocrine cells

The gastrointestinal tract is lined with a monolayer of cells that undergo continuous and rapid renewal, in contrast to the epithelia of the other endoderm-derived organs such as liver and lung that differentiate early in life and turn over slowly in adulthood (Cardoso and Lu, 2006, Darlington, 1999, Fausto et al., 2006, Rawlins and Hogan, 2008, Zaret, 2002). Enteroendocrine cells found in the gastrointestinal tract express several hormones, and even transcriptional regulators, originally

Notch signaling in enteroendocrine cell differentiation

Notch is a transmembrane receptor that mediates local cell–cell communication and coordinates a signaling cascade schematized in Fig. 2 (Lai, 2004). Unlike other receptors, Notch functions both at the cell surface to receive signals and in the nucleus to regulate gene expression (Lai, 2004). The key players of the Notch pathway in mammals are the ligands (Delta and Jagged), the receptor (Notch 1 through 4) and a transcription factor (RBP-Jκ) that translates the signaling process into target

bHLH transcription factors in enteroendocrine cell differentiation

Three proendocrine bHLH transcription factors, all targets of Notch signaling, have been shown to contribute to enteroendocrine cell differentiation through loss-of-function studies in mice (Jenny et al., 2002, Lee et al., 2002, Naya et al., 1997, Yang et al., 2001, Shroyer et al., 2007). Math1, Neurogenin 3 (Ngn3) and NeuroD are all related to the Drosophila atonal gene, which is critical in neural differentiation in the fly (Ben-Arie et al., 1997, Lee et al., 1995, Sommer et al., 1996). This

Zinc-finger transcription factors in enteroendocrine cell differentiation

The zinc-finger containing transcription factor Gfi1 is expressed in scattered cells throughout the developing intestine epithelium. Once the intestine matures, Gfi1 is found mainly in the crypts but also in some villi in the small intestine (Shroyer et al., 2005). Double immunostaining analysis showed that Gfi1 expression is restricted to enteroendocrine lineages (Shroyer et al., 2005). In addition, Gfi1 is expressed within the crypt in Math1-dependent progenitors, and Gfi1 expression is

Homeodomain transcription factors in enteroendocrine cell differentiation

As mentioned briefly above, many homeobox genes including Isl-1, Pdx1, Nkx6.1 and Nkx2.2 have been shown to be involved in enteroendocrine cell differentiation. Isl-1 transactivates somatostatin expression in islet tumor cells in vitro (Leonard et al., 1992) and its expression is restricted to G/D precursors (gastrin/somatostatin co-expressing cells) and a subpopulation of somatostatin cells in the stomach (Larsson et al., 1995). This implies that Isl-1 could be involved in the asymmetric

Paired and homeodomain transcription factors in enteroendocrine cell differentiation

Two paired box (Pax) genes, Pax4 and Pax6, are expressed throughout the gastrointestinal tract during development. Mice deficient for either Pax4 or Pax6 fail to properly elaborate pancreatic endocrine cells (Sosa-Pineda et al., 1997, St-Onge et al., 1997). Similar to their role in the pancreas, the two genes also control important stages of enteroendocrine cell differentiation in the gut.

Deletion of Pax4 affects enteroendocrine cell development only in the rostral gastrointestinal tract. In

NK class and homeodomain transcription factors in enteroendocrine cell differentiation

Nkx6.1 expression is detected in the gastric mucosa, but not in the duodenum (Jensen et al., 1996). The majority of cells expressing Nkx6.1 are serotonin-expressing cells, with a smaller population expressing gastrin (Oster et al., 1998). In Pdx1-deficient mice, Nkx6.1 expression is absent, indicating Pdx1 acts upstream of Nkx6.1 in the enteroendocrine cell program (Oster et al., 1998).

Nkx2.2 expression is first detected in the proximal forestomach and then in scattered cells throughout the

Summary and future directions

Many unanswered questions remain regarding how enteroendocrine cells are specified in the gastrointestinal tract, and if it might be possible to control their relative contribution with therapeutic benefit. Unlike endocrine cells in the pancreas, which cluster together to form islets, enteroendocrine cells are scattered as individual cells throughout the gastrointestinal mucosa. Very little is known about what directs the region-specific expression of hormones in the gut. Although the functions

Acknowledgements

The authors thank Dr. Joshua R. Friedman for critical reading of the manuscript and Johanna Murray for providing the immunostaining images. Related work in KHK's laboratory was supported by NIH grants R01-DK053839 and R01-DK055342, and in CLM's laboratory by NIH grant R01-DK078606 and JDRF 2-2007-703.

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