Chapter Four - Transcriptional Networks and Signaling Pathways that Govern Vertebrate Intestinal Development

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Abstract

The vertebrate intestine is a complex and highly specialized organ comprising tissues derived from all three germ layers. While a description of the morphological events underlying the consolidation and organization of the endoderm, mesoderm, and ectoderm-derived cells into a multi-layered, continuously renewing organ has been available for several decades, only recently has a strong genetic framework for this process started to emerge, and as yet it remains incomplete. This review highlights the roles played by a number of transcription factors and signaling pathways in the development of the vertebrate intestine from the moment the definitive endoderm is formed. These molecular pathways often interact with each other and play multiple roles at different stages of intestinal formation. What is currently attracting considerable attention in the field is the realization that the deregulated activities of these same pathways often play a key role in the initiation and progression of a number of complex, serious intestinal diseases, including inflammatory bowel disease and cancer.

Introduction

The alimentary or gastrointestinal (GI) tract is a long tubular system comprising the esophagus, stomach, small intestine (which is itself sub-divided into the duodenum, jejunum, and ileum), and the large intestine or colon, arranged in series along the rostrocaudal axis. Each successive organ exhibits distinct morphological features and expresses unique differentiated cell types that enable the tube to carry out its essential functions of ingestion, digestion, nutrient absorption, elimination, and metabolic homeostasis. In all vertebrates the inner surface of the intestine is irregular, with ridges and projections of various shapes and sizes to increase the surface area over which digestion and absorption can take place. The adult human intestinal tract is approximately 8 m in length and has a surface area typically in the region of 200 m2 (the area of a tennis court) — quite an achievement for an organ that starts out early in development as a tiny ribbon of endoderm.

The mature intestine comprises four concentric layers of tissue: the mucosa, submucosa, muscularis propria, and serosa (Fig. 4.1). The inner layer is the mucosa (Fig. 4.1, inset), which comprises the intestinal epithelium, a supporting lamina propria, and the muscularis mucosae, which contains several layers of smooth muscle fibers. The endoderm-derived intestinal epithelium provides a water-tight barrier between the outside world and the body. It encloses a lumen through which all ingested material is transported and is the primary site of nutrient absorption. In mammals, the surface area of the intestinal epithelium is vastly increased by the formation of elaborate structural compartments called crypts of Lieberkühn (hereafter called crypts) and villi. The crypts are goblet-shaped invaginations which penetrate the submucosa. In contrast, the finger-like villi are substantially longer and project into the lumen. These two inter-connected compartments accommodate cells exhibiting all aspects of cellular behavior including self-renewal, cell-fate determination, proliferation, differentiation, migration, and apoptosis. Multipotential stem cells are found towards the bottom of the crypts and these give rise to four distinct intestinal cell lineages and support the continuous renewal of the intestinal lining throughout life. In intimate contact with the epithelium is the mesoderm-derived lamina propria, a loose connective tissue containing α-smooth muscle actin-positive intestinal sub-epithelial myofibroblasts (ISEMFs) (Powell et al., 1999), blood and lymphatic capillaries, and large numbers of leukocytes.

The second layer is the submucosa, a mesoderm-derived, mesenchymal tissue which connects the mucosa to the muscle wall. It comprises a collagenous extracellular matrix containing larger blood and lymphatic vessels and huge numbers of immune cells (the intestine is the largest immune organ in the body). The third layer is the muscular wall or muscularis propria. It is also mesoderm-derived and contains several layers of smooth muscle arranged as inner circular and outer longitudinal muscle fibers. In concert with the neural crest (ectoderm)-derived enteric neurons, which populate the intestine in the submucosa region and between the muscle layers, the two muscle layers arranged at right angles to each other generate the peristaltic movements that propel the food along the gut. Finally, the fourth layer, or serosa, comprises a loose supporting tissue carrying the major vessels and nerves and lined by a simple squamous epithelium.

As mentioned above, the epithelial lining of the GI tract is derived from endoderm, one of the three principal germ layers. The endoderm contributes cells not only to the GI tract but also to the respiratory tract and a number of derivative organs, including the pancreas, liver, biliary tree, lung, thymus, and thyroid gland. Vertebrate endoderm organ development is an area of intense study and over the last decade studies in zebrafish and mouse, in particular, have enhanced our understanding of the genetic control of endoderm organ development.

The aim of this chapter is to document the chronological sequence of morphological events that take place during intestinal development—from the transformation of a ribbon of undifferentiated endoderm to a three-dimensional tube with rostrocaudal, dorsoventral, and radial asymmetry (Fig. 4.1), and to describe the genetic pathways that govern these events. Most information is derived from studies in mice but additional insights gleaned from studies in other model organisms, particularly zebrafish, are also included. As has been appreciated for some time, pathways governing developmental processes are frequently disrupted in a wide variety of pathological states, most notably cancer, as well as in a number of inherited syndromes. Where relevant, a discussion of the roles played by some of the intestinal development genes in the etiology of pathological states is highlighted.

Section snippets

Formation of the Definitive Endoderm

The initial specification of endoderm cells from the pluripotent cells of the epiblast in early vertebrate embryos depends on Nodal signaling (Fig. 4.2A). Nodal is a member of the transforming growth factor (TGF)-β superfamily. A gradient of Nodal ligand activity, which in Xenopus is generated by the T-box transcription factor (TF), vegT (Xanthos et al., 2001), stimulates the production of multiple TFs, including Gata5, Mezzo, Mixer (for reviews see Schier, 2003, Tam et al., 2003, Zorn and

Tube formation

In mammals and the chick, the formation of a gut tube with a lumen is initiated by the ventrally directed invagination of the endoderm at its anterior and posterior ends. This gives rise to two ventral pockets, or portals, of endoderm known as the anterior intestinal portal (AIP; Fig. 4.2B, C) and the caudal intestinal portal (CIP; Fig. 4.2C). Reciprocal rostrocaudal movements of these invaginations (Fig. 4.2C) then serve to elongate the endodermal layer until they fuse in the midline of the

Establishment of the Crypt–Villus Axis

Radial asymmetry, in the form of the cryptvillus axis, is a hallmark of the mature intestinal epithelium (Fig. 4.1). As mentioned previously, in the small intestine (formed from the midgut), this axis comprises two distinct morphological but contiguous compartments, the crypts and the villi. In contrast, the large intestine or colon (formed from the hindgut) ultimately develops crypts without villi, requiring the physically separated processes of cell proliferation and differentiation to take

Establishing the Stem Cell Niche and Homeostasis in the Intestinal Epithelium

At the time of birth, epithelial proliferation in mice remains restricted to the inter-villus regions and the more elaborate crypt structures have yet to form. This process takes place over the course of the next few weeks of post-natal life, when the epithelial cells of the inter-villus pockets penetrate into the mesenchyme to form mature crypts, which gradually increase in number by crypt fission. The mature intestinal epithelium then embarks on a process of renewal which is continuous

Role of Intestinal Development Pathways in Cancer

This review has highlighted a few signaling pathways that play critical roles during vertebrate intestinal development, most notably Wnt/β-catenin, Hh, Eph, Notch, and Bmp signaling. In the normal adult intestinal epithelium, these pathways continue to interact with each other to maintain tight control over the opposing processes of proliferation and differentiation along the cryptvillus axis. However, it is clear that with the passage of time, specific components of these pathways are

Acknowledgments

I apologize to the many authors who have contributed knowledge to our understanding of the genetic control of intestinal development whose work is not cited here. I thank Janna Taylor for figure preparation and Tony Burgess, Matthias Ernst, Tanya de Jong-Curtain, and Yeliz Rifat for helpful comments on the manuscript. Work in my laboratory on the genetic basis of intestinal development and colon cancer is funded by the National Health and Medical Research Council (NHMRC), Australia through

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