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Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000.

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Developmental Biology. 6th edition.

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The Pharynx

The function of the embryonic endoderm is to construct the linings of two tubes within the body. The first tube, extending throughout the length of the body, is the digestive tube. Buds from this tube form the liver, gallbladder, and pancreas. The second tube, the respiratory tube, forms as an outgrowth of the digestive tube, and it eventually bifurcates into two lungs. The digestive and respiratory tubes share a common chamber in the anterior region of the embryo; this region is called the pharynx. Epithelial outpockets of the pharynx give rise to the tonsils and the thyroid, thymus, and parathyroid glands.

The respiratory and digestive tubes are both derived from the primitive gut (Figure 15.26). As the endoderm pinches in toward the center of the embryo, the foregut and hindgut regions are formed. At first, the oral end is blocked by a region of ectoderm called the oral plate, or stomodeum. Eventually (at about 22 days in human embryos), the stomodeum breaks, thereby creating the oral opening of the digestive tube. The opening itself is lined by ectodermal cells. This arrangement creates an interesting situation, because the oral plate ectoderm is in contact with the brain ectoderm, which has curved around toward the ventral portion of the embryo. These two ectodermal regions interact with each other. The roof of the oral region forms Rathke's pouch and becomes the glandular part of the pituitary gland. The neural tissue on the floor of the diencephalon gives rise to the infundibulum, which becomes the neural portion of the pituitary. Thus, the pituitary gland has a dual origin, which is reflected in its adult functions.

Figure 15.26. Formation of the human digestive system, depicted at about (A) 16 days, (B) 18 days, (C) 22 days, and (D) 28 days.

Figure 15.26

Formation of the human digestive system, depicted at about (A) 16 days, (B) 18 days, (C) 22 days, and (D) 28 days. (After Crelin 1961.)

The anterior endodermal portion of the digestive and respiratory tubes begins in the pharynx. Here, the mammalian embryo produces four pairs of pharyngeal pouches (Figure 15.27). Between these pouches are the pharyngeal arches. The first pair of pharyngeal pouches becomes the auditory cavities of the middle ear and the associated eustachian tubes. The second pair of pouches gives rise to the walls of the tonsils. The thymus is derived from the third pair of pharyngeal pouches; it will direct the differentiation of T lymphocytes during later stages of development. One pair of parathyroid glands is also derived from the third pair of pharyngeal pouches, and the other pair is derived from the fourth. In addition to these paired pouches, a small, central diverticulum is formed between the second pharyngeal pouches on the floor of the pharynx. This pocket of endoderm and mesenchyme will bud off from the pharynx and migrate down the neck to become the thyroid gland. The respiratory diverticulum sprouts from the pharyngeal floor, between the fourth pair of pharyngeal pouches, to form the lungs, as we will see below.

Figure 15.27. Endodermal development of a human embryo.

Figure 15.27

Endodermal development of a human embryo. The color illustration below is a sagittal view of the 6-week embryo. The stomach region has begun to dilate, and the pancreas is represented by two buds that will eventually fuse. The upper row of illustrations (more...)

The Digestive Tube and Its Derivatives

Posterior to the pharynx, the digestive tube constricts to form the esophagus, which is followed in sequence by the stomach, small intestine, and large intestine. The endodermal cells generate only the lining of the digestive tube and its glands; mesodermal mesenchyme cells will surround this tube to provide the muscles for peristalsis.

As Figure 15.27 shows, the stomach develops as a dilated region close to the pharynx. More caudally, the intestines develop, and the connection between the intestine and yolk sac is eventually severed. At the caudal end of the intestine, a depression forms where the endoderm meets the overlying ectoderm. Here, a thin cloacal membrane separates the two tissues. It eventually ruptures, forming the opening that will become the anus.

Specification of the gut tissue

As the endodermal tubes form, the endodermal epithelium is able to respond differently to different regionally specific mesodermal mesenchymes. This enables the digestive tube and respiratory tube to develop different structures in different regions. Thus, as the mammalian digestive tube meets new mesenchymes, it differentiates into esophagus, stomach, small intestine, and colon (Gumpel-Pinot et al. 1978; Fukumachi and Takayama 1980; Kedinger et al. 1990).

The specificity of the mesoderm is thought to be controlled by its interactions with the endodermal tube during earlier stages of development. As the gut tube begins to form from the anterior and posterior ends, it induces the splanchnic mesoderm to become regionally specific. Roberts and colleagues (1995, 1997) have implicated Sonic hedgehog in this specification. Early in development, the expression of Shh is limited to the posterior endoderm of the hindgut and the pharynx. As the tubes extend toward the center of the embryo, the domains of Shh expression increase, eventually extending throughout the gut endoderm. Shh is secreted in different concentrations at different sites, and its target appears to be the mesoderm surrounding the gut tube. (The splanchnic mesoderm cells around the gut contain Patched protein, the receptor for the Hedgehog protein family, in their cell membranes.) In the hindgut, the secretion of Shh by the endoderm induces in the mesoderm a nested set of “posterior” Hox gene expression. As in the vertebrae (see Chapter 11), the anterior borders of the expression pattern delineate the morphological boundaries of the regions that will form the cloaca, large intestine, cecum, mid-cecum (at the midgut/hindgut border), and the posterior portion of the midgut (Figure 15.28; Roberts et al. 1995; Yokouchi et al. 1995). When Hox-containing viruses cause the misexpression of these Hox genes in the mesoderm, the mesodermal cells alter the differentiation of the adjacent endoderm (Roberts et al. 1998). Thus, the endodermal expression of Shh in the hindgut seems to induce a nested expression of Hox genes in the mesoderm. These Hox genes probably specify the mesoderm so that it can interact with the endodermal tube and specify its regions.

Figure 15.28. Regional specification of the visceral mesoderm through interactions with the posterior gut endoderm.

Figure 15.28

Regional specification of the visceral mesoderm through interactions with the posterior gut endoderm. (A) The expression and secretion of Sonic hedgehog in the endoderm generates a nested set of Hox gene expression in the adjacent mesoderm. After the (more...)

Liver, pancreas, and gallbladder

The endoderm also forms the lining of three accessory organs that develop immediately caudal to the stomach. The hepatic diverticulum is the tube of endoderm that extends out from the foregut into the surrounding mesenchyme. The mesenchyme induces this endoderm to proliferate, to branch, and to form the glandular epithelium of the liver. A portion of the hepatic diverticulum (that region closest to the digestive tube) continues to function as the drainage duct of the liver, and a branch from this duct produces the gallbladder (Figure 15.29).

Figure 15.29. Pancreatic development in humans.

Figure 15.29

Pancreatic development in humans. (A) At 30 days, the ventral pancreatic bud is close to the liver primordium. (B) By 35 days it begins migrating posteriorly, and (C) comes into contact with the dorsal pancreatic bud during the sixth week of development. (more...)

The pancreas develops from the fusion of distinct dorsal and ventral diverticula. Both of these primordia arise from the endoderm immediately caudal to the stomach, and as they grow, they come closer together and eventually fuse. In humans, only the ventral duct survives to carry digestive enzymes into the intestine. In other species (such as the dog), both the dorsal and ventral ducts empty into the intestine.

The Respiratory Tube

The lungs are a derivative of the digestive tube, even though they serve no role in digestion. In the center of the pharyngeal floor, between the fourth pair of pharyngeal pouches, the laryngotracheal groove extends ventrally (Figure 15.31). This groove then bifurcates into the two branches that form the paired bronchi and lungs. The laryngotracheal endoderm becomes the lining of the trachea, the two bronchi, and the air sacs (alveoli) of the lungs.

Figure 15.31. Partitioning of the foregut into the esophagus and respiratory diverticulum during the third and fourth weeks of human gestation.

Figure 15.31

Partitioning of the foregut into the esophagus and respiratory diverticulum during the third and fourth weeks of human gestation. (A) Lateral view, end of week 3. (B, C) Ventral views, week 4. (After Langman 1981.)

The lungs are an evolutionary novelty, and they are among the last of the mammalian organs to fully differentiate. The lungs must be able to draw in oxygen at the newborn's first breath. To accomplish this, the alveolar cells secrete a surfactant into the fluid bathing the lungs. This surfactant, consisting of phospholipids such as sphingomyelin and lecithin, is secreted very late in gestation, and it usually reaches physiologically useful levels at about week 34 of human gestation. The surfactant enables the alveolar cells to touch one another without sticking together. Thus, infants born prematurely often have difficulty breathing and have to be placed on respirators until their surfactant-producing cells mature.

As in the digestive tube, the regional specificity of the mesenchyme determines the differentiation of the developing respiratory tube. In the developing mammal, the respiratory epithelium responds in two distinct fashions. In the region of the neck, it grows straight, forming the trachea. After entering the thorax, it branches, forming the two bronchi and then the lungs. The respiratory epithelium can be isolated soon after it has split into two bronchi, and the two sides can be treated differently. Figure 15.32 shows the result of such an experiment. The right bronchial epithelium retained its lung mesenchyme, whereas the left bronchus was surrounded with tracheal mesenchyme (Wessells 1970). The right bronchus proliferated and branched under the influence of the lung mesenchyme, whereas the left bronchus continued to grow in an unbranched manner. Moreover, the differentiation of the respiratory epithelia into trachea or lung cells depends on the mesenchyme it encounters (Shannon et al. 1998). Thus, the respiratory epithelium is extremely malleable and can differentiate according to its mesenchymal instructions.

Figure 15.32. Ability of presumptive lung epithelium to differentiate with respect to the source of the inducing mesenchyme.

Figure 15.32

Ability of presumptive lung epithelium to differentiate with respect to the source of the inducing mesenchyme. After embryonic mouse lung epithelium had branched into two bronchi, the entire rudiment was excised and cultured. The right bronchus was left (more...)


15.4 Induction of the lung. The induction of the lung also involves the interplay between FGFs and Shh. However, it appears to be different from the induction of either the pancreas or the liver.

The Extraembryonic Membranes

In reptiles, birds, and mammals, embryonic development has taken a new evolutionary direction. Reptiles evolved a mechanism for laying eggs on dry land, thus freeing them to explore niches that were not close to water. To accomplish this, the embryo produces four sets of extraembryonic membranes to mediate between it and the environment (see Chapter 11). Even though most mammals have evolved placentas instead of shells, the basic pattern of extraembryonic membranes remains the same. In developing reptiles, birds, and mammals, there initially is no distinction between embryonic and extraembryonic domains. However, as the body of the embryo takes shape, the epithelia at the border between the embryo and the extraembryonic domain divide unequally to create body folds that isolate the embryo from the yolk and delineate which areas are to be embryonic and which extraembryonic (Miller et al. 1994, 1999). These membranous folds are formed by the extension of ectodermal and endodermal epithelium underlain with lateral plate mesoderm. The combination of ectoderm and mesoderm, often referred to as the somatopleure, forms the amnion and chorion; the combination of endoderm and mesoderm—the splanchnopleure—forms the yolk sac and allantois. The endodermal or ectodermal tissue supplies functioning epithelial cells, and the mesoderm generates the essential blood supply to and from this epithelium. The formation of these folds can be followed in Figure 15.33.

Figure 15.33. Schematic drawings of the extraembryonic membranes of the chick.

Figure 15.33

Schematic drawings of the extraembryonic membranes of the chick. The embryo is cut longitudinally, and the albumin and shell coatings are not shown. (A) A 2-day embryo. (B) A 3-day embryo. (C) Detailed schematic diagram of the caudal (hind) region of (more...)

The amnion and chorion

The first problem of a land-dwelling egg is desiccation. Embryonic cells would quickly dry out if they were not in an aqueous environment. This environment is supplied by the amnion. The cells of this membrane secrete amnionic fluid; thus, embryogenesis still occurs in water. This evolutionary adaptation is so significant and characteristic that reptiles, birds, and mammals are grouped together as the amniote vertebrates, or amniotes.

The second problem of a land-dwelling egg is gas exchange. This exchange is provided for by the chorion, the outermost extraembryonic membrane. In birds and reptiles, this membrane adheres to the shell, allowing the exchange of gases between the egg and the environment. In mammals, as we have seen, the chorion has developed into the placenta, which has evolved endocrine, immune, and nutritive functions in addition to those of respiration.

The allantois and yolk sac

The third problem for a land-dwelling egg is waste disposal. The allantois stores urinary wastes and also helps mediate gas exchange. In reptiles and birds, the allantois becomes a large sac, as there is no other way to keep the toxic by-products of metabolism away from the developing embryo. In some amniote species, such as chickens, the mesodermal layer of the allantoic membrane reaches and fuses with the mesodermal layer of the chorion to create the chorioallantoic membrane. This extremely vascular envelope is crucial for chick development and is responsible for transporting calcium from the eggshell into the embryo for bone production (Tuan 1987). In mammals, the size of the allantois depends on how well nitrogenous wastes can be removed by the chorionic placenta. In humans (in which nitrogenous wastes can be efficiently removed through the maternal circulation), the allantois is a vestigial sac. In pigs, however, the allantois is a large and important organ.

The fourth problem that a land-dwelling egg has to solve is nutrition. The yolk sac is the first extraembryonic membrane to be formed, as it mediates nutrition in developing birds and reptiles. It is derived from splanchnopleural cells that grow over the yolk to enclose it. The yolk sac is connected to the midgut by an open tube, the yolk duct, so that the walls of the yolk sac and the walls of the gut are continuous. The blood vessels within the mesoderm of the splanchnopleure transport nutrients from the yolk into the body, for yolk is not taken directly into the body through the yolk duct. Rather, endodermal cells digest the protein into soluble amino acids that can then be passed on to the blood vessels within the yolk sac. Other nutrients, including vitamins, ions, and fatty acids, are stored in the yolk sac and transported by the yolk sac blood vessels into the embryonic circulation. In these ways, the four extraembryonic membranes enable the amniote embryo to develop on land.

Snapshot Summary: Lateral Mesoderm and Endoderm


The lateral plate mesoderm splits into two layers. The dorsal layer is the somatic (parietal) mesoderm, which underlies the ectoderm and forms the somatopleure. The ventral layer is the splanchnic (visceral) mesoderm, which overlies the endoderm and forms the splanchnopleure.


The space between these two layers is the body cavity, the coelom.


The heart arise from splanchnic mesoderm on both sides of the body. This region of cells is called the cardiogenic mesoderm.


The Nkx2-5 transcription factor is important in specifying cells to become cardiogenic mesoderm. These cells migrate from the sides to the midline of the embryo, in the neck region.


Cardiogenic mesoderm forms the endocardium (which is continuous with the blood vessels) and the myocardium (the muscular component of the heart).


The endocardial tubes form separately and then fuse. The looping of the heart transforms the original anterior-posterior polarity of the heart tube into a right-left polarity.


In mammals, fetal circulation differs dramatically from adult circulation. When the infant takes its first breath, changes in air pressure close the foramen ovale through which blood had passed from the right to the left atrium. At that time, the lungs, rather than the placenta, become the source of oxygen.


Blood vessel formation is constrained by physiological, evolutionary, and physical parameters. The subdividing of a large vessel into numerous smaller ones allows rapid transport of the blood to regions of gas and nutrient diffusion.


Blood vessels are constructed by two processes, vaculogenesis and angiogenesis. Vasculogenesis involves the condensing of visceral mesoderm cells to form blood islands. The outer cells of these islands become endothelial (blood vessel) cells. Angiogenesis involves remodeling existing blood vessels.


Numerous paracrine factors are essential in blood vessel formation. FGF2 is needed for specifying the angioblasts. VEGF is essential for the differentiation of angioblasts. Angiopoietin-1 allows the smooth muscle cells (and smooth muscle-like pericytes) to cover the vessels. Ephrin ligands and Eph receptor tyrosine kinases are critical for capillary bed formation.


The pluripotential hematopoietic stem cell generates other pluripotential stem cells, as well as lineage-restricted stem cells. It gives rise to both blood cells and lymphocytes.


The CFU-S is a blood stem cell that can generate the more committed stem cells for the different blood lineages. Hematopoietic inductive microenvironments determine the direction of the blood cell differentiation.


In mammals, embryonic blood stem cells are provided by the blood islands near the yolk. The definitive adult blood stem cells come from the aorta-gonad-mesonephros region within the embryo.


The endoderm constructs the digestive tube and the respiratory tube.


Four pairs of pharyngeal pouches become the endodermal lining of the eustacian tube, tonsils, thymus, and parathyroid glands. The thyroid also forms in this region of endoderm.


The gut tissue forms by reciprocal interactions between the endoderm and the mesoderm. Sonic hedgehog from the endoderm appears to play a role in inducing a nested pattern of Hox gene expression in the mesoderm surrounding the gut. The regionalized mesoderm then instructs the endodermal tube to become the different organs of the digestive tube.


The pancreas forms in a region of endoderm that lacks Sonic hedgehog expression. The Pdx1 transcription factor is expressed in this region.


The respiratory tube is derived as an outpocketing of the digestive tube. The regional specificity of the mesenchyme it meets determines whether the tube remains straight (as in the tracheae) or branches (as in the alveoli).


The yolk sac and allantois are derived from the splanchnopleure. The yolk sac (in birds and reptiles) allows yolk nutrients to pass into the blood. The allantois collects nitrogenous wastes.


The chorion and amnion are made by the somatopleure. In birds and reptiles, the chorion abuts the shell and allows for gas exchange. The amnion in birds, reptiles, and mammals bathes the embryo in amnionic fluid.

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The Specification of Liver and Pancreas.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2000, Sinauer Associates.
Bookshelf ID: NBK10107


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