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Fourth to Eighth Weeks of Human Development


All major external and internal structures are established during the fourth to eighth weeks. By the end of this embryonic period, the main organ systems have started to develop. As the tissues and organs form, the shape of the embryo changes, and by the end of this period, the embryo has a distinctly human appearance. Because the tissues and organs are differentiating rapidly, exposure of embryos to teratogens during this period may cause major birth defects. Teratogens are agents (such as some drugs and viruses) that produce or increase the incidence of major birth defects (see Chapter 20 ).

Phases of Embryonic Development

Human development is divided into three phases, which to some extent are interrelated:

  • The first phase is growth , which involves cell division and elaboration of cell products.

  • The second phase is morphogenesis , the development of shape, size, and other features of a particular organ or part or the whole body. Morphogenesis is a complex molecular process controlled by the expression and regulation of specific genes in an orderly sequence. Changes in cell fate, cell shape, and cell movement allow the cells to interact with each other during the formation of tissues and organs.

  • The third phase is differentiation , during which cells are organized in a precise pattern of tissues and organs that are capable of performing specialized functions.

Folding of Embryo

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A significant event in the establishment of body form is folding of the flat trilaminar embryonic disc into a somewhat cylindric embryo ( Fig. 5.1 ). Folding occurs in the median and horizontal planes and results from the rapid growth of the embryo. The growth rate at the sides of the embryonic disc fails to keep pace with the rate of growth in the long axis as the embryo increases rapidly in length. Folding at the cranial and caudal ends and sides of the embryo occurs simultaneously. Concurrently, there is relative constriction at the junction of the embryo and umbilical vesicle.

Fig. 5.1, Drawings of folding of embryos during the fourth week. A 1 , Dorsal view of an embryo early in the fourth week. Three pairs of somites are visible. The continuity of the intraembryonic coelom and extraembryonic coelom is illustrated on the right side by removal of a part of the embryonic ectoderm and mesoderm. B 1 , C 1 , and D 1 , Lateral views of embryos at 22, 26, and 28 days, respectively. A 2 to D 2 , Sagittal sections at the plane shown in A 1 . A 3 to D 3 , Transverse sections at the levels indicated in A 1 to D 1 .

Folding of Embryo in the Median Plane

Folding of the ends of the embryo produces head and tail folds that result in the cranial and caudal regions moving ventrally as the embryo elongates cranially and caudally (see Fig. 5.1 A 2 to D 2 ).

Head Fold

At the beginning of the fourth week, the neural folds in the cranial region form the primordium of the brain (see Fig. 5.1 A 2 and B 2 ). Initially, the developing brain projects dorsally into the amniotic cavity, the fluid-filled cavity inside the amnion (the innermost membrane around the embryo). The amniotic cavity contains amniotic fluid and the embryo. Later, the developing forebrain grows cranially beyond the oropharyngeal membrane and overhangs the developing heart ( Fig. 5.2 B and C ). At the same time, the septum transversum , primordial heart, pericardial coelom, and oropharyngeal membrane move onto the ventral surface of the embryo. During folding, part of the endoderm of the umbilical vesicle is incorporated into the embryo as the foregut (primordium of pharynx, esophagus, and lower respiratory system) (see Fig. 5.2 C , and also see Chapter 11 ). The foregut lies between the forebrain and primordial heart, and the oropharyngeal membrane separates the foregut from the stomodeum , the primordial mouth ( Fig. 5.3 B , and see Fig. 5.2 C ).

Fig. 5.2, Folding of cranial end of embryo. A , Dorsal view of embryo at 21 days. B , Sagittal section of the cranial part of the embryo at the plane shown in A . Observe the ventral movement of the heart in B and C . C , Sagittal section of an embryo at 26 days. Note that the septum transversum, primordial heart, pericardial coelom, and oropharyngeal membrane have moved onto the ventral surface of the embryo. Observe also that part of the umbilical vesicle is incorporated into the embryo as the foregut.

Fig. 5.3, Drawings of the effect of the head fold on the intraembryonic coelom. A , Lateral view of an embryo (24 to 25 days) during folding, showing the large forebrain, ventral position of the heart, and communication between the intraembryonic and extraembryonic parts of the coelom. B , Schematic drawing of an embryo (26 to 27 days) after folding, showing the pericardial cavity ventrally, the pericardioperitoneal canals running dorsally on each side of the foregut, and the intraembryonic coelom in communication with the extraembryonic coelom.

After folding of the head, the septum transversum lies caudal to the heart, where it subsequently develops into the central tendon of the diaphragm , the partition between the abdominal and thoracic cavities (see Fig. 5.3 B , and also see Chapter 8 ). The head fold also affects the arrangement of the embryonic coelom (primordium of the body cavity). Before folding, the coelom consists of a flattened, horseshoe-shaped cavity (see Fig. 5.1 A 1 ). After folding, the pericardial coelom lies ventral to the heart and cranial to the septum transversum (see Fig. 5.2 B and C ). At this stage, the intraembryonic coelom communicates widely on each side with the extraembryonic coelom (see Figs. 5.1 A 3 and 5.3 A and B ).

Tail Fold

Folding of the caudal end of the embryo results primarily from growth of the distal part of the neural tube, the primordium of the spinal cord ( Fig. 5.4 A and B ). As the embryo grows, the caudal eminence (tail region) projects over the cloacal membrane , the future site of the anus (see Figs. 5.3 A and 5.4 B ). During folding, part of the endodermal germ layer is incorporated into the embryo as the hindgut , the descending colon and rectum (see Fig. 5.4 B ).

Fig. 5.4, Folding of caudal end of the embryo. A , Sagittal section of caudal part of the embryo at the beginning of the fourth week. B , Similar section at the end of the fourth week. Note that part of the umbilical vesicle is incorporated into the embryo as the hindgut and that the terminal part of the hindgut has dilated to form the cloaca. Observe also the change in position of the primitive streak, allantois, cloacal membrane, and connecting stalk.

The terminal part of the hindgut soon dilates slightly to form the cloaca , the rudiment of the urinary bladder and rectum (see Fig. 5.4 B , and also see Chapters 11 and 12 ). Before folding, the primitive streak lies cranial to the cloacal membrane (see Fig. 5.4 A ); after folding, it lies caudal to it (see Fig. 5.4 B ). The connecting stalk (primordium of the umbilical cord) is now attached to the ventral surface of the embryo (see Fig. 5.4 A ), and the allantois, or the diverticulum of the umbilical vesicle, is partially incorporated into the embryo (see Fig. 5.4 A and B ).

Folding of Embryo in the Horizontal Plane

Folding of the sides of the developing embryo produces right and left lateral folds (see Fig. 5.1 A 3 to D 3 ). Lateral folding is produced by the rapidly growing spinal cord and somites. The primordia of the ventrolateral abdominal wall fold toward the median plane, rolling the edges of the embryonic disc ventrally and forming a roughly cylindric embryo (see Fig. 5.6 A ). As the abdominal wall forms, part of the endoderm germ layer is incorporated into the embryo as the midgut , the primordium of the small intestine (see Fig. 5.1 C 2 , and also see Chapter 11 ).

Initially, there is a wide connection between the midgut and umbilical vesicle (see Fig. 5.1 A 2 ); however, after lateral folding, the connection is reduced, forming an omphaloenteric duct (see Fig. 5.1 C 2 ). The region of attachment of the amnion to the ventral surface of the embryo is also reduced to a relatively narrow umbilical region (see Fig. 5.1 D 2 and D 3 ). As the umbilical cord forms from the connecting stalk (see Fig. 5.1 B 2 and D 2 ), ventral fusion of the lateral folds reduces the region of communication between the intraembryonic and extraembryonic coelomic cavities to a narrow communication (see Fig. 5.1 C 2 ). As the amniotic cavity expands and obliterates most of the extraembryonic coelom, the amnion forms the epithelial covering of the umbilical cord (see Fig. 5.1 D 2 ).

Germ Layer Derivatives

The three germ layers (ectoderm, mesoderm, and endoderm) formed during gastrulation ( Fig. 5.5 ) give rise to the primordia of all tissues and organs. The specificity of the germ layers, however, is not rigidly fixed. The cells of each germ layer divide, migrate, aggregate, and differentiate in patterns as they form the various organ systems. The main germ layer derivatives are as follows (see Fig. 5.5 ):

  • Ectoderm gives rise to the central nervous system; peripheral nervous system; sensory epithelia of the eyes, ears, and nose; epidermis and its appendages (hair and nails); mammary glands; pituitary gland; subcutaneous glands; and enamel of the teeth. Neural crest cells , derived from neuroectoderm , the central region of early ectoderm, eventually give rise to or participate in the formation of many cells types and organs, including cells of the spinal cord, cranial nerves (V, VII, IX, and X), and autonomic ganglia; ensheathing cells of the peripheral nervous system; pigment cells of the dermis; muscles, connective tissues, and bones of pharyngeal arch origin; suprarenal medulla; and meninges (coverings) of the brain and spinal cord.

  • Mesoderm gives rise to connective tissue, cartilage, bone, striated and smooth muscles, heart, blood, and lymphatic vessels; kidneys; ovaries; testes; genital ducts; serous membranes lining the body cavities (pericardial, pleural, and peritoneal membranes); spleen; and cortex of the suprarenal glands.

  • Endoderm gives rise to the epithelial lining of the digestive and respiratory tracts; parenchyma (connective tissue framework) of the tonsils; thyroid and parathyroid glands; thymus, liver, and pancreas; epithelial lining of the urinary bladder and most of the urethra; and epithelial lining of the tympanic cavity, tympanic antrum, and pharyngotympanic tube (see Fig. 5.5 ).

Fig. 5.5, Schematic drawing of derivatives of the three germ layers: ectoderm, endoderm, and mesoderm. Cells from these layers contribute to the formation of different tissues and organs.

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