Intestinal development and differentiation

Abstract

In this review, we present an overview of intestinal development and cellular differentiation of the intestinal epithelium. The review is separated into two sections: Section one summarizes organogenesis of the small and large intestines, including endoderm and gut tube formation in early embryogenesis, villus morphogenesis, and crypt formation. Section two reviews cell fate specification and differentiation of each cell type within the intestinal epithelium. Growth factor and transcriptional networks that regulate these developmental processes are summarized.

Figure 1. Early development of the intestine

Endoderm formation is first detected during gastrulation which, in mice, occurs from e5 to e7.5 and is shown at left in the medial to lateral plane. Cells in the transient mesendoderm state, but not ectoderm, migrate through the primitive streak and form either mesoderm or endoderm with anterior-posterior patterning depending on timing and level of exposure to Nodal. After gastrulation, the endoderm can be seen as a simple epithelial sheet underlying the mesoderm (ventral to the notochord and lateral plate mesoderm). Endodermal tubulogenesis occurs in mice from about e8 through e9.5 and is shown along the anterior-posterior axis. After formation of the endodermal sheet, the anterior and posterior ends indent and subsequently form pockets, termed the anterior intestinal portal (AIP) and caudal intestinal portal (CIP). The AIP (giving rise to foregut) and CIP (giving rise to hindgut) grow and extend deeper while the lateral midgut endoderm (not pictured, out of the plane of the image) folds ventrally to complete the tube. Splanchnic mesoderm from the lateral plate surrounds the folding endoderm during this tubulogenesis stage to enclose the gut tube and connect it to the dorsal body wall. The images at right labeled Growth and Villus formation are shown as medial to lateral cross sections of the endoderm tube. At e10.5 the intestinal endoderm is seen as a compact pseudostratified epithelium; over the next 3 days the tube lengthens and widens. Villus formation initiates in a rostral to caudal wave at approximately e14.5, as clusters of mesenchymal cells form below the epithelium and extend toward the center of the lumen, creating villi.

Figure 2. Model for intestinal differentiation

(Right) Cartoon depicting crypt structure with individual cell types shown. Cells migrate out of the crypt and onto the villus as they terminally differentiate, except Paneth cells which reside intercalated among the stem cells at the crypt base. (Left) A diagram summarizing key events in intestinal epithelial differentiation. Genes are shown next to cells in which they are expressed or have a role in their differentiation/maturation. Self-renewing stem cells (red and pink) receive signals to produce either absorptive enterocytes or secretory cells (enteroendocrine, goblet, Paneth and tuft cells). Notch induces stem cells to express Hes1 which represses Atoh1 and allows these cells to become enterocytes (white). Atoh1 expressing secretory progenitor cells (light purple) coexpress Dll1, a Notch ligand. Neurog3 specifies enteroendocrine progenitors from Atoh1-specified secretory progenitors. Gfi1 represses Neurog3 to direct progenitors to differentiate as goblet (blue) or Paneth (yellow) cells. Little is known about factors required for tuft cell (dark purple) differentiation.