Patterning the Gut

Initial patterning of the gut endoderm begins during the period of late gastrulation, as the sheet of newly formed endoderm begins to form a gut tube. After initial broad patterning into anterior and posterior domains by nodal and fibroblast growth factor-4 (FGF-4), respectively, the overall organization of the gut gradually takes shape. Much of the patterning and of early morphogenesis of the gut occurs in response to the actions of several sets of molecular signals. As development and early organogenesis proceed, the same signaling molecules are reused. Paradoxically, the same molecule may play opposite roles in the same area, but at different times (i.e., it may first act as a stimulator, and then, within hours or days, it may function as an inhibitor).

Patterning of the broad foregut area occurs through the inhibition of Wnt signals (Fig. 15.1). The foregut domain is then marked by the expression of the transcription factors, Sox-2, Hhex, and Foxa-2. In contrast, a mix of activity by Wnts, FGFs, and bone morphogenetic proteins (BMPs), along with retinoic acid, represses foregut identity and maintains the regional identity of the hindgut. This is marked by the expression of the transcription factor Cdx-2 throughout the broad hindgut and the later expression of Pdx-1 in the midgut as this region emerges as a separate entity. Cdx-2 acts upstream of a broad range of Hox activity (Fig. 15.2) that is expressed throughout the gut. The activity of specific signaling molecules is associated with important transition points along the gut. FGF-4 is strongly expressed near the foregut-midgut boundary (around the duodenal-jejunal junction), and FGF-10 is associated with the establishment of the cecum.

Largely through the action of Cdx-2, the orderly expression of homeobox-containing genes then takes over in the regional patterning of the digestive system (see Fig. 15.2).

Mice bearing mutant copies of some of these genes develop several of the common structural malformations of the digestive tract that occur in humans. More dramatically, mice deficient in retinoic acid, a broad early patterning molecule, fail to form lungs and show severe defects of other posterior foregut derivatives, such as the stomach, duodenum, and liver. Development of the gut tube proper involves continuous elongation, herniation past the body wall, and rotation and folding for efficient packing into the body cavity, as well as histogenesis and later functional maturation.

By the end of the first month, small endodermal diverticula, which represent primordia of the major digestive glands, can be identified (Fig. 15.3). (Development of the pharynx and its glandular derivatives is discussed in Chapter 14.) The digestive glands and respiratory structures grow in complex branching patterns, resembling fractals, as the result of continuous epithelial-mesenchymal interactions. These interactions also occur in the developing digestive tube itself, with specific regional mesenchymal influences determining the character of the epithelium lining that part of the digestive tract.

Each of the glandular derivatives of the digestive tract, as well as the major regions along the gut, is the result of a specific response by a small population of founder cells for each organ to a set of environmental inductive signals. At a first level, certain regions of the gut must be prepared to be either responsive or refractive to these signals. For example, after the overall foregut is specified by the suppression of Wnt and FGF signals, transforming growth factor-β (TGF-β) signaling restricts the specification of foregut endoderm to allow the prehepatic and prepancreatic endoderm to remain receptive to inductive signals. By the same token, other influences on the dorsal side of the foregut repress the ability of these cells to become liver or pancreas.

During neurulation, as the head bends sharply to create the foregut, the ventral foregut endoderm is closely opposed to two mesodermal masses: the cardiac mesoderm and the primordium of the septum transversum (see Fig. 15.4). High levels of FGF, secreted by the cardiac mesoderm, and also retinoic acid induce the formation of the liver, lung bud, and thyroid (see Fig. 15.4). BMP-4 from the mesoderm of the septum transversum is also required for liver induction. By contrast, endodermal movements carry the preventral pancreas cells far enough from the cardiac mesoderm to expose them to a low level of FGF, thus allowing the ventral pancreas to develop. For the dorsal pancreas to develop, locally produced sonic hedgehog (shh) must be inactivated by activin and FGF emanating from the notochord. In addition, retinoic acid from the somitic mesoderm is needed for induction of the dorsal pancreas. Meanwhile, in the hindgut, the actions of Wnt and other signaling molecules repress the expression of genes, such as Hhex and Pdx1, which are essential for formation of the liver and pancreas, respectively.

Induction of these organs is marked by the activation of transcription factors specific for the organ and stage of development of that organ. Some of these factors are schematically represented in Figure 15.4B.

Formation of the Esophagus

Just caudal to the most posterior pharyngeal pouches of a 4-week-old embryo, the pharynx becomes abruptly narrowed, and a small ventral outgrowth (lung bud) appears (see Fig. 6.20). The region of foregut just caudal to the lung bud is the esophagus. This segment is initially very short, with the stomach seeming to reach almost to the pharynx. In the second month of development, during which the gut elongates considerably, the esophagus assumes nearly postnatal proportions in relation to the location of the stomach.

Although the esophagus grossly resembles a simple tube, it undergoes a series of striking differentiative changes at the tissue level. In its earliest stages, the endodermal lining epithelium of the esophagus is stratified columnar. By 8 weeks, the epithelium has partially occluded the lumen of the esophagus, and large vacuoles appear (Fig. 15.5). In succeeding weeks, the vacuoles coalesce, and the esophageal lumen recanalizes, but with multilayered ciliated epithelium. During the fourth month, this epithelium finally is replaced with the stratified squamous epithelium that characterizes the mature esophagus.

Deeper in the esophageal wall, layers of muscle also differentiate in response to inductive signals from the gut endoderm. Very early (5 weeks’ gestation), the primordium of the inner circular muscular layer of esophagus is recognizable, and by 8 weeks, the outer longitudinal layer of muscle begins to take shape. The esophageal wall contains smooth and skeletal muscle. The smooth muscle cells differentiate from the local splanchnic mesoderm associated with the gut, and the skeletal musculature is derived from paraxial mesoderm. All esophageal musculature is innervated by the vagus nerve (cranial nerve X).

The cross-sectional structure of the esophagus, similar to that of the rest of the gut, is organized into discrete layers. The innermost layer (mucosa) consists of the epithelium, derived from endoderm, and an underlying layer of connective tissue, the lamina propria (see Fig. 15.5C and D). A thick layer of loose connective tissue (submucosa) separates the mucosa from the outer layers of muscle (usually smooth muscle, with the exception of the upper esophagus). This radial organization is regulated by the epithelial expression of shh, acting through its receptor, patched, and BMP-4. Shh inhibits the formation of smooth muscle in the submucosal layer of the esophagus. Farther from the source of the endodermal shh, smooth muscle can differentiate in the outer wall of the intestine. How the developing smooth muscle layer of the mucosa (muscularis mucosae) escapes this inhibitory influence is also unclear. Intestinal mesenchyme can spontaneously differentiate into smooth muscle in the absence of an epithelium (which produces shh). Because in humans the muscularis mucosae differentiates considerably later than the outer muscular layers, it is possible that inhibitory levels of shh are reduced by that time.

Formation of the Stomach

Formation of the stomach within the foregut is first specified by the action of the transcription factors Hoxa-5 and Barx-1, which inhibits the posteriorizing effects of Wnt signaling in the region of the future stomach. A second phase of specification follows, in which a descending posterior-to-anterior gradient of FGF-10, produced in the gastric mesoderm, begins the process of regional differentiation of the glandular character of the gastric epithelium.

Very early in the formation of the digestive tract, the stomach is recognizable as a dilated region with a shape remarkably similar to that of the adult stomach (see Fig. 15.3). The early stomach is suspended from the dorsal body wall by a portion of the dorsal mesentery called the dorsal mesogastrium. It is connected to the ventral body wall by a ventral mesentery that also encloses the developing liver (Fig. 15.6).

When the stomach first appears, its concave border faces ventrally, and its convex border faces dorsally. Two concomitant positional shifts bring the stomach to its adult configuration. The first is an approximately 90-degree rotation about its craniocaudal axis so that its originally dorsal convex border faces left, and its ventral concave border faces right. The other positional shift consists of a minor tipping of the caudal (pyloric) end of the stomach in a cranial direction so that the long axis of the stomach is positioned diagonally across the body (Fig. 15.7).

During rotation of the stomach, the dorsal mesogastrium is carried with it, thus leading to the formation of a pouchlike structure called the omental bursa (bursa is a Latin word meaning “sac” or “pouch”). Both the spleen and the tail of the pancreas are embedded in the dorsal mesogastrium (see Fig. 15.6). Another viewpoint suggests that the right pneumatoenteric recess, a projection from the pleural cavity into the dorsal mesogastrium, persists as the omental bursa.

As the stomach rotates, the dorsal mesogastrium and the omental bursa that it encloses enlarge dramatically. Soon, part of the dorsal mesogastrium, which becomes the greater omentum, overhangs the transverse colon and portions of the small intestines as a large, double flap of fatty tissue (Fig. 15.8). The two sides of the greater omentum ultimately fuse and obliterate the omental bursa within the greater omentum. The rapidly enlarging liver occupies an increasingly large portion of the ventral mesentery.

At the histological level, the gastric mucosa begins to take shape late in the second month with the appearance of folds (rugae) and the first gastric pits. During the early fetal period, the individual cell types that characterize the gastric mucosa begin to differentiate. Biochemical and cytochemical studies have shown the gradual functional differentiation of specific cell types during the late fetal period. In most mammals, including humans, cells of the gastric mucosa begin to secrete hydrochloric acid shortly before birth.

The caudal end of the stomach is physiologically separated from the small intestine by the muscular pyloric sphincter. Formation of the pyloric sphincter is directed by the transcription factors Sox-9 and Nkx 2.5, whose expression in the area of pyloric mesoderm is stimulated by BMP-4 signals. In addition, several Hox genes are needed to make each of the three major sphincters (pyloric, ileocecal, and anal) in the digestive tract.

Clinical Correlation 15.1 presents malformations of the esophagus and stomach.

Clinical Correlation 15.1   Malformations of the Esophagus and Stomach

Esophagus

The most common anomalies of the esophagus are associated with abnormalities of the developing respiratory tract (see p. 364). Other rare anomalies are stenosis and atresia of the esophagus. Stenosis is usually attributed to abnormal recanalization of the esophagus after epithelial occlusion of its lumen. Experimental evidence suggests that abnormal separation of the early notochord from the dorsal foregut endoderm is often associated with esophageal atresia, possibly through the incorporation of some of the dorsal foregut cells into an abnormal notochord. Atresia of the esophagus is most commonly associated with abnormal development of the respiratory tract. In both these conditions, impaired swallowing by the fetus can lead to an excessive accumulation of amniotic fluid (polyhydramnios). Just after birth, a newborn with these anomalies commonly has difficulty swallowing milk, and regurgitation and choking while drinking are indications for examination of the patency of the esophagus.

Stomach

Pyloric Stenosis

Pyloric stenosis, which seems to be more physiological than anatomical, consists of hypertrophy of the circular layer of smooth muscle that surrounds the pyloric (outlet) end of the stomach. The hypertrophy causes a narrowing (stenosis) of the pyloric opening and impedes the passage of food. Several hours after a meal, the infant violently vomits (projectile vomiting) the contents of the meal. The enlarged pyloric end of the stomach can often be palpated on physical examination. Although pyloric stenosis is commonly treated by a simple surgical incision through the layer of circular smooth muscle of the pylorus, the hypertrophy sometimes diminishes without treatment by several weeks after birth. The pathogenesis of this defect remains unknown, but it seems to have a genetic basis. Pyloric stenosis is more common in male than in female infants, and the incidence has been reported as 1 in 200 to 1 in 1000 infants.

Heterotopic Gastric Mucosa

Heterotopic gastric mucosa has been found in a variety of otherwise normal organs (Fig. 15.10). This condition is often clinically significant because if the heterotopic mucosa secretes hydrochloric acid, ulcers can form in unexpected locations. Many cases of heterotopic tissue within the gastrointestinal tract are now thought to be caused by the inappropriate expression of genes that are characteristic of other regions of the gut, but the question remains: What is the basis of the inappropriate gene expression, and why does it often occur within a very restricted area? Given the recognition of increasingly complex networks of genetic control in the gut, it is not difficult to imagine that on occasion normal developmental controls go awry, but understanding the genetic basis of specific instances of ectopic mucosa still remains elusive.

Development of the Spleen

Development of the spleen is not well understood. Initially, two bilaterally symmetrical organ fields are reduced by regression to one on the left. The spleen is first recognizable as a mesenchymal condensation in the dorsal mesogastrium at 4 weeks and is initially closely associated with the developing dorsal pancreas. Initiation of splenic development requires the cooperative action of a basic helix-loop-helix protein (Pod-1) and a homeobox-containing protein (Bapx-1), acting through another transcription factor, Pbx-1. Such a combination is emerging as a common theme in the initiation of development of several organs. These substances act on the downstream molecules Nkx 2.5 and the oncogene Hox-11 (T-cell leukemia homeobox-1) in early splenic development (Fig. 15.9).

The splenic primordium consists of a condensation of mesenchyme covered by the overlying mesothelium of the dorsal mesogastrium, both of which contribute to the stroma of the spleen. Its normal left-sided location is determined early by the mechanisms that dictate heart asymmetry; Nkx 2.5, an important determinant of early heart development, is also expressed in the splenic primordium. Hematopoietic cells move into the spleen in the late embryonic period, and from the third to fifth months, the spleen and the liver serve as major sites of hematopoiesis during the first trimester of pregnancy. Later, the splenic primordium becomes infiltrated by lymphoid cells, and by the fourth month, the complex vascular structure of the red pulp begins to take shape.

Formation of the Intestines

The intestines are formed from the posterior part of the foregut, the midgut, and the hindgut (Table 15.1). Table 15.2 summarizes the chronology of major stages in the development of the digestive tract. Two points of reference are useful in understanding the gross transformation of the primitive gut tube from a relatively straight cylinder to the complex folded arrangement characteristic of the adult intestinal tract. The first is the yolk stalk, which extends from the floor of the midgut to the yolk sac. In the adult, the site of attachment of the yolk stalk is on the small intestine about 2 feet cranial to the junction between small and large intestine (ileocecal junction). On the dorsal side of the primitive gut, an unpaired ventral branch of the aorta, the superior mesenteric artery, and its branches feed the midgut (see Fig. 15.7). The superior mesenteric artery itself serves as a pivot point about which later rotation of the gut occurs.

By 5 weeks, rapid growth of the gut tube causes it to buckle out in a hairpinlike loop. The growth in length results in large part from the effect of FGF-9, which is produced by the epithelium and stimulates proliferation of the fibroblasts in the intestinal walls. The major change that causes the intestines to assume their adult positions is a counterclockwise rotation of the caudal limb of the intestinal loop (with the yolk stalk attachment and superior mesenteric artery as reference points) around the cephalic limb from its ventral aspect. The main consequence of this rotation is to bring the future colon across the small intestine so that it can readily assume its C-shaped position along the ventral abdominal wall (see Fig. 15.7). Behind the colon, the small intestine undergoes great elongation and becomes packed in its characteristic position in the abdominal cavity.

The rotation and other positional changes of the gut occur partly because the length of the gut increases more than the length of the embryo. From almost the first stages, the volume of the expanded gut tract is greater than the body cavity can accommodate. Consequently, the developing intestines herniate into the body stalk (the umbilical cord after further development) (Fig. 15.11). Intestinal herniation begins by 6 or 7 weeks of embryogenesis. By 9 weeks, the abdominal cavity has enlarged sufficiently to accommodate the intestinal tract, and the herniated intestinal loops begin to move through the intestinal ring back into the abdominal cavity. Coils of small intestine return first. As they do, they force the distal part of the colon, which was never herniated, to the left side of the peritoneal cavity, thus establishing the definitive position of the descending colon. After the small intestine has assumed its intra-abdominal position, the herniated proximal part of the colon also returns, with its cecal end swinging to the right and downward (see Fig. 15.7).

During these coilings, herniations, and return movements, the intestines are suspended from the dorsal body wall by a mesentery (Fig. 15.12). Experimentation has shown that looping of the intestine is caused principally by tension-compression relationships between the intestine and its dorsal mesentery. When the intestine is separated from the mesentery, the normal looping does not occur. As the intestines assume their definitive positions within the body cavity, their mesenteries follow. Parts of the mesentery associated with the duodenum and colon (mesoduodenum and mesocolon) fuse with the peritoneal lining of the dorsal body wall.

Starting in the sixth week, the primordium of the cecum becomes apparent as a swelling in the caudal limb of the midgut (see Fig. 15.7). In succeeding weeks, the cecal enlargement becomes so prominent that the distal small intestine enters the colon at a right angle. The sphincterlike boundary at the cecum between the small and large intestines, similar to that in other regions of the gut, is regulated by a high concentration of Cdx-2 and a sequence of Hox gene expression. In mice, deletion of Hoxd4, Hoxd8 to Hoxd11, and Hoxd13 results in the absence of this region. When the overall pattern has been set by combinations of Hox genes, cecal development depends on an interaction between FGF-9 produced by the cecal epithelium and FGF-10 produced by the overlying mesoderm.

The tip of the cecum elongates, but its diameter does not increase in proportion to the rest of the cecum. This wormlike appendage is aptly called the vermiform appendix.

Partitioning of the Cloaca

In the early embryo, the caudal end of the hindgut terminates in the endodermally lined cloaca, which, in lower vertebrates, serves as a common termination for the digestive and urogenital systems. The cloaca also includes the base of the allantois, which later expands as a common urogenital sinus (see Chapter 16). A cloacal (proctodeal) membrane consisting of apposed layers of ectoderm and endoderm acts as a barrier between the cloaca and an ectodermal depression known as the proctodeum (Fig. 15.13). A shelf of mesodermal tissue called the urorectal septum is situated between the hindgut and the base of the allantois. During weeks 6 and 7, the urorectal septum advances toward the cloacal membrane. At the same time, lateral mesodermal ridges extend into the cloaca.

The combined ingrowth of the lateral ridges and growth of the urorectal septum toward the cloacal membrane divide the cloaca into the rectum and urogenital sinus (see Fig. 15.13B). Double mutants of Hoxa13 and Hoxd13 result in the absence of cloacal partitioning, along with hypodevelopment of the phallus (genital tubercle). In addition, they lead to the absence of the smooth muscle component of the anal sphincter. According to classic embryology, the urorectal septum fuses with the cloacal membrane, thus dividing it into an anal membrane and a urogenital membrane before these membranes break down (see Fig. 15.13C). Other research suggests that the cloacal membrane undergoes apoptosis and breaks down without its fusion with the urorectal septum. The area where the urorectal septum and lateral mesodermal folds fuse with the cloacal membrane becomes the perineal body, which represents the partition between the digestive and urogenital systems.

The actual anal canal consists of a craniocaudal transition from columnar colonic (rectal) epithelium to a transitional region of cloacally derived endodermal epithelium leading into a zone of squamous epithelium that merges with the external perianal skin. These zones are surrounded by the smooth muscle internal anal sphincter.

Histogenesis of the Intestinal Tract

Shortly after its initial formation, the intestinal tract consists of a simple layer of columnar endodermal epithelium surrounded by a layer of splanchnopleural mesoderm. Three major phases are involved in the histogenesis of the intestinal epithelium: (1) an early phase of epithelial proliferation and morphogenesis, (2) an intermediate period of cellular differentiation in which the distinctive cell types characteristic of the intestinal epithelium appear, and (3) a final phase of biochemical and functional maturation of the different types of epithelial cells. The mesenchymal wall of the intestine also differentiates into several layers of highly innervated smooth muscle and connective tissue. An overall craniocaudal gradient of differentiation is present within the developing intestine.

The endoderm of the early foregut is capable of producing cell types other than those of the gut tube itself, such as liver cells. A two-phase series of inhibitory influences from the gut mesoderm restricts the overlying endoderm to forming only the appropriate epithelial cell types through the activity of the transcription factors Foxa-2 (formerly called hepatic nuclear factor-3) and GATA-4, which are essential for formation of anterior regions of endoderm.

Early in the second month, the epithelium of the small intestine begins a phase of rapid proliferation that causes the epithelium temporarily to occlude the lumen by 6 to 7 weeks’ gestation. Within a couple of weeks, recanalization of the intestinal lumen has occurred. At about this time, small, cracklike secondary lumina appear beneath the surface of the multilayered epithelium, and aggregates of mesoderm push into the epithelium. A combination of coalescence of the secondary lumina with continued mesenchymal upgrowth beneath the epithelium results in the formation of numerous fingerlike intestinal villi, which greatly increase the absorptive surface of the intestinal surface. By this time, the epithelium has transformed from a stratified into a simple columnar type.

With the formation of villi, pitlike intestinal crypts form at the bases of the villi. Toward the bottom of the crypts are epithelial intestinal stem cells, which, in response to Wnt signaling, have a high rate of mitosis and serve as the source of epithelial cells for the entire intestinal surface (Fig. 15.14). Despite the presence of four to six stem cells per crypt, it has been shown that each crypt is monoclonal (i.e., all the existing cells are descendants of a single stem cell from earlier in development). Toward the top of a crypt, shh and Indian hedgehog (Ihh) signaling stimulates the activity of BMP. This BMP has two main functions. It counteracts the effects of Wnt and thus keeps proliferation deep in the crypt, and it also facilitates cellular differentiation. Aided in part by an ephrin-eph gradient, progeny of the stem cells make their way up the wall of the crypt as multipotential transit amplifying cells, which, under the influence of the Delta-Notch system, begin to differentiate into the four main mature cell types of the intestinal epithelium (see Fig. 15.14). These cells then both differentiate and migrate toward the tip of the villus, until after about 4 days they die and are shed into the intestinal lumen as they are replaced below by new epithelial cells derived from the crypts. Human intestinal epithelial cells develop the intrinsic capacity for apoptosis by 18 to 20 weeks of gestation.

By the end of the second trimester of pregnancy, all cell types found in the adult intestinal lining have differentiated, but many of these cells do not possess adult functional patterns. Several specific biochemical patterns of differentiation are present by 12 weeks’ gestation and mature during the fetal period. For example, lactase, an enzyme that breaks down the disaccharide lactose (milk sugar), is one of the digestive enzymes synthesized in the fetal period in anticipation of the early postnatal period during which the newborn subsists principally on the mother’s milk. Further biochemical differentiation of the intestine occurs after birth, often in response to specific dietary patterns.

Histodifferentiation of the intestinal tract is not an isolated property of the individual tissue components of the intestinal wall. During the early embryonic period and sometimes into postnatal life, the epithelial and mesodermal components of the intestinal wall communicate by inductive interactions. In region-specific manners, these interactions involve hedgehog signaling (shh for the foregut and midgut and Ihh for the hindgut) from the endodermal epithelium. BMP signaling from the mesoderm is involved in positioning the crypts and villi in the small intestine and the glands of the colon. Interspecies recombination experiments show that the gut mesoderm exerts a regional influence on intestinal epithelial differentiation (e.g., whether the epithelium differentiates into a duodenal or colonic phenotype). When regional determination is set, however, the controls for biochemical differentiation of the epithelium are inherent. This pattern of inductive influence and the epithelial reaction are similar to those outlined earlier for dermal-epidermal interactions in the developing skin (see Chapter 9).

Final enzymatic differentiation of intestinal absorptive cells is strongly influenced by glucocorticoids, and the underlying mesoderm seems to mediate this hormonal effect. In a converse inductive influence, the intestinal endoderm, through the action of shh signaling, induces the differentiation of smooth muscle from mesenchymal cells in the wall of the intestine.

Although the intestine develops many functional capabilities during the fetal period, no major digestive function occurs until feeding begins after birth. The intestines of the fetus contain a greenish material called meconium (see Fig. 18.9), which is a mixture of lanugo hairs and vernix caseosa sloughed from the skin, desquamated cells from the gut, bile secretion, and other materials swallowed with the amniotic fluid.

Formation of Enteric Ganglia

As outlined in Chapter 12, the enteric ganglia of the gut are derived from neural crest. Pax-3–expressing cells from the vagal neural crest migrate into the foregut and spread in a wavelike fashion throughout the entire length of the gut. Slightly later, cells from the sacral crest enter the hindgut and intermingle with cells derived from the vagal neural crest. The migratory properties of vagal crest cells are much more pronounced than are those of cells from the sacral crest. Initially, the vagal crest cells migrate throughout the mesenchyme of the gut, but as the smooth muscle of the intestines begins to differentiate, the migrating vagal crest cells become preferentially distributed between the smooth muscle and the serosa, where the myenteric plexuses form. They are absent from the connective tissue of the submucosa because of the inhibiting effects of shh, secreted by the epithelial cells. During migration through the gut, the population of neural crest cells undergoes a massive expansion until the number of enteric neurons ultimately exceeds the number of neurons present in the spinal cord. Glial cells also differentiate from neural crest precursors in the gut, but the environmental factors that contribute to the differentiation of neural crest cells in the gut wall remain poorly understood.

Clinical Correlation 15.2

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