Gut Development Proteins

 Gut Development Proteins Background

The gut epithelium is under constant development, with differentiation of stem cells and progenitors occurring throughout the life of an organism. Many pathways traditionally thought of as development pathways are used during adult stages to regulate proliferation, differentiation, and apoptosis. Some of the critical pathways include Wnt, Notch, and hedgehog, which are used throughout embryogenesis and adulthood.

The architecture of the mouse intestine is established during middle to late gestation. It begins as a psuedostratified epithelium of endodermal origin, which proliferates rapidly and converts to a single-layered epithelium around embryonic day 14.5 (E14.5) in the mouse. The epithelium then forms protrusions, pre-villi, and cell cycling is restricted to shallow pockets between the villi, pre-crypts. At the same time, surrounding mesoderm differentiates into smooth muscle and connective tissue, acting in support of the epithelium. The fetal gut is completely formed around E18.5, and not until the third week of life do the proliferative pockets invade the submucosa and form mature crypts of Lieberkuhn.

In the adult intestine, the epithelium forms a contiguous two-dimensional sheet where new cells are added from the crypts, migrate up the villus, and are eliminated by apoptosis when they reach the villus tip a few days later. Intestinal stem cells reside above the crypt base with proliferative progenitors above and differentiated cells along the villus. Of the differentiated cells, only Paneth cells take a different path, moving down to the base of the crypt. In the colon, there is an absence of Paneth cells, so the stem cells inhabit the base of the crypts.

Throughout life, the epithelial stem cells self-renew, cycling only when needed to produce the proliferative progenitors with a limited self-renewal capacity. All cells in an adult crypt derive from a single stem cell. The proliferative progenitors soon become committed progenitors, which differentiate upon reaching the crypt-villus junction to become enteroendocrine, goblet or absorptive epithelial cells moving up the villus or Paneth cells that move to the base of the crypt. β-catenin and TCF activity are the main effectors of the proliferation/differentiation switch, with Tcf4 transcriptional regulation responsible for stem cell self-renewal.

Each of the cell types within the small intestine has a unique function, and differentiation of these distinctive cells requires specific signals. The cell fate determination is not well characterized but is believed to occur through at least four successive binary decisions affected by expression of at least three transcription factors, Mathl, Hes1, and Gfi1. The absorptive epithelial cells, also known as enterocytes, require expression of Hes1 to act as a negative regulator, whereas expression of Mathl acts as an activator, committing cells to the secretory lineage, which encompasses Paneth, goblet, and enteroendocrine cells. Additional expression of Gfi1 will commit secretory lineage cells to either Paneth or goblet cells with non-Gfi1 expressing cells remaining enteroendocrine cells.

The functions of the four cell types of the small intestine vary. Comprising about 80% of the epithelial cells are enterocytes. These columnar cells form lateral junctions with nearby cell and use apical microvilli to increase the surface area for absorption. The primary function of these cells is to degrade nutrients, and in the mouse enterocytes turnover every 3 days. Goblet cells represent about 5% of intestinal epithelial cells and are scattered from mid-crypt throughout the villus. The identifying characteristic of goblet cells is the presence of mucin within the cytoplasm; this mucous provides a protective barrier against intestinal contents. Like the enterocytes, goblet cells turnover about every 3 days. Enteroendocrine cells are responsible for producing hormones that assist in regulating gastrointestinal (Gl) motility and also have a rapid turnover. In contrast, Paneth cells are only turned over about every 20 days, which may have something to do with their position at the base of the crypt. These columnar epithelial cells with apical cytoplasmic granules are responsible for the antimicrobial defense of the small intestine. Though the secretory lineage functions as protectors of the intestine, loss of the secretory lineage is not lethal, as Mtgr1-null mice do not maintain these cell types but are able to live and function normally.