Embryonic and fetal ages are expressed in terms of weeks from fertilization, commonly called conception. The period of time required for full development of a fetus in utero is referred to as gestation (gestare = “to carry” or “to bear”). It can be subdivided into distinct gestational periods. The first 2 weeks of prenatal development are referred to as the pre-embryonic stage. A developing human is referred to as an embryo during weeks 3–8, and a fetus from the ninth week of gestation until birth. In this section, we’ll cover the pre-embryonic and embryonic stages of development, which are characterized by cell division, migration, and differentiation. By the end of the embryonic period, all of the organ systems are structured in rudimentary form, although the organs themselves are either nonfunctional or only semi-functional.

Overview

As the zygote travels toward the uterus, it undergoes numerous cleavages in which the number of cells doubles (blastomeres). Upon reaching the uterus, the conceptus has become a tightly packed sphere of cells called the morula, which then forms into a blastocyst consisting of an inner cell mass within a fluid-filled cavity surrounded by trophoblasts. The blastocyst implants in the uterine wall, the trophoblasts fuse to form a syncytiotrophoblast, and the conceptus is enveloped by the endometrium. Four embryonic membranes form to support the growing embryo: the amnion, the yolk sac, the allantois, and the chorion. The chorionic villi of the chorion extend into the endometrium to form the fetal portion of the placenta. The placenta supplies the growing embryo with oxygen and nutrients; it also removes carbon dioxide and other metabolic wastes.

Following implantation, embryonic cells undergo gastrulation, in which they differentiate and separate into an embryonic disc and establish three primary germ layers (the endoderm, mesoderm, and ectoderm). Through the process of embryonic folding, the fetus begins to take shape. Neurulation starts the process of the development of structures of the central nervous system and organogenesis establishes the basic plan for all organ systems.

Following fertilization, the zygote and its associated membranes, together referred to as the conceptus, continue to be projected toward the uterus by peristalsis and beating cilia. During its journey to the uterus, the zygote undergoes five or six rapid mitotic cell divisions. Although each cleavage results in more cells, it does not increase the total volume of the conceptus (image). Each daughter cell produced by cleavage is called a blastomere (blastos = “germ,” in the sense of a seed or sprout).

Approximately 3 days after fertilization, a 16-cell conceptus reaches the uterus. The cells that had been loosely grouped are now compacted and look more like a solid mass. The name given to this structure is the morula (morula = “little mulberry”). Once inside the uterus, the conceptus floats freely for several more days. It continues to divide, creating a ball of approximately 100 cells, and consuming nutritive endometrial secretions called uterine milk while the uterine lining thickens. The ball of now tightly bound cells starts to secrete fluid and organize themselves around a fluid-filled cavity, the blastocoel. At this developmental stage, the conceptus is referred to as a blastocyst. Within this structure, a group of cells forms into an inner cell mass, which is fated to become the embryo. The cells that form the outer shell are called trophoblasts (trophe = “to feed” or “to nourish”). These cells will develop into the chorionic sac and the fetal portion of the placenta (the organ of nutrient, waste, and gas exchange between mother and the developing offspring).

The inner mass of embryonic cells is totipotent during this stage, meaning that each cell has the potential to differentiate into any cell type in the human body. Totipotency lasts for only a few days before the cells’ fates are set as being the precursors to a specific lineage of cells.

At the end of the first week, the blastocyst comes in contact with the uterine wall and adheres to it, embedding itself in the uterine lining via the trophoblast cells. Thus begins the process of implantation, which signals the end of the pre-embryonic stage of development (image). Implantation can be accompanied by minor bleeding. The blastocyst typically implants in the fundus of the uterus or on the posterior wall. However, if the endometrium is not fully developed and ready to receive the blastocyst, the blastocyst will detach and find a better spot. A significant percentage (50–75 percent) of blastocysts fail to implant; when this occurs, the blastocyst is shed with the endometrium during menses. The high rate of implantation failure is one reason why pregnancy typically requires several ovulation cycles to achieve.

When implantation succeeds and the blastocyst adheres to the endometrium, the superficial cells of the trophoblast fuse with each other, forming the syncytiotrophoblast, a multinucleated body that digests endometrial cells to firmly secure the blastocyst to the uterine wall. In response, the uterine mucosa rebuilds itself and envelops the blastocyst (image). The trophoblast secretes human chorionic gonadotropin (hCG), a hormone that directs the corpus luteum to survive, enlarge, and continue producing progesterone and estrogen to suppress menses. These functions of hCG are necessary for creating an environment suitable for the developing embryo. As a result of this increased production, hCG accumulates in the maternal bloodstream and is excreted in the urine. Implantation is complete by the middle of the second week. Just a few days after implantation, the trophoblast has secreted enough hCG for an at-home urine pregnancy test to give a positive result.

Most of the time an embryo implants within the body of the uterus in a location that can support growth and development. However, in one to two percent of cases, the embryo implants either outside the uterus (an ectopic pregnancy) or in a region of uterus that can create complications for the pregnancy. If the embryo implants in the inferior portion of the uterus, the placenta can potentially grow over the opening of the cervix, a condition call placenta previa.

Disorders of the…

Development of the Embryo
In the vast majority of ectopic pregnancies, the embryo does not complete its journey to the uterus and implants in the uterine tube, referred to as a tubal pregnancy. However, there are also ovarian ectopic pregnancies (in which the egg never left the ovary) and abdominal ectopic pregnancies (in which an egg was “lost” to the abdominal cavity during the transfer from ovary to uterine tube, or in which an embryo from a tubal pregnancy re-implanted in the abdomen). Once in the abdominal cavity, an embryo can implant into any well-vascularized structure—the rectouterine cavity (Douglas’ pouch), the mesentery of the intestines, and the greater omentum are some common sites.

Tubal pregnancies can be caused by scar tissue within the tube following a sexually transmitted bacterial infection. The scar tissue impedes the progress of the embryo into the uterus—in some cases “snagging” the embryo and, in other cases, blocking the tube completely. Approximately one half of tubal pregnancies resolve spontaneously. Implantation in a uterine tube causes bleeding, which appears to stimulate smooth muscle contractions and expulsion of the embryo. In the remaining cases, medical or surgical intervention is necessary. If an ectopic pregnancy is detected early, the embryo’s development can be arrested by the administration of the cytotoxic drug methotrexate, which inhibits the metabolism of folic acid. If diagnosis is late and the uterine tube is already ruptured, surgical repair is essential.

Even if the embryo has successfully found its way to the uterus, it does not always implant in an optimal location (the fundus or the posterior wall of the uterus). Placenta previa can result if an embryo implants close to the internal os of the uterus (the internal opening of the cervix). As the fetus grows, the placenta can partially or completely cover the opening of the cervix (image). Although it occurs in only 0.5 percent of pregnancies, placenta previa is the leading cause of antepartum hemorrhage (profuse vaginal bleeding after week 24 of pregnancy but prior to childbirth).

Embryonic Membranes - During the second week of development, with the embryo implanted in the uterus, cells within the blastocyst start to organize into layers. Some grow to form the extra-embryonic membranes needed to support and protect the growing embryo: the amnion, the yolk sac, the allantois, and the chorion.

At the beginning of the second week, the cells of the inner cell mass form into a two-layered disc of embryonic cells, and a space—the amniotic cavity—opens up between it and the trophoblast (image). Cells from the upper layer of the disc (the epiblast) extend around the amniotic cavity, creating a membranous sac that forms into the amnion by the end of the second week. The amnion fills with amniotic fluid and eventually grows to surround the embryo. Early in development, amniotic fluid consists almost entirely of a filtrate of maternal plasma, but as the kidneys of the fetus begin to function at approximately the eighth week, they add urine to the volume of amniotic fluid. Floating within the amniotic fluid, the embryo—and later, the fetus—is protected from trauma and rapid temperature changes. It can move freely within the fluid and can prepare for swallowing and breathing out of the uterus.

On the ventral side of the embryonic disc, opposite the amnion, cells in the lower layer of the embryonic disk (the hypoblast) extend into the blastocyst cavity and form a yolk sac. The yolk sac supplies some nutrients absorbed from the trophoblast and also provides primitive blood circulation to the developing embryo for the second and third week of development. When the placenta takes over nourishing the embryo at approximately week 4, the yolk sac has been greatly reduced in size and its main function is to serve as the source of blood cells and germ cells (cells that will give rise to gametes). During week 3, a finger-like outpocketing of the yolk sac develops into the allantois, a primitive excretory duct of the embryo that will become part of the urinary bladder. Together, the stalks of the yolk sac and allantois establish the outer structure of the umbilical cord.

The last of the extra-embryonic membranes is the chorion, which is the one membrane that surrounds all others. The development of the chorion will be discussed in more detail shortly, as it relates to the growth and development of the placenta.

As the third week of development begins, the two-layered disc of cells becomes a three-layered disc through the process of gastrulation, during which the cells transition from totipotency to multipotency. The embryo, which takes the shape of an oval-shaped disc, forms an indentation called the primitive streak along the dorsal surface of the epiblast. A node at the caudal or “tail” end of the primitive streak emits growth factors that direct cells to multiply and migrate. Cells migrate toward and through the primitive streak and then move laterally to create two new layers of cells. The first layer is the endoderm, a sheet of cells that displaces the hypoblast and lies adjacent to the yolk sac. The second layer of cells fills in as the middle layer, or mesoderm. The cells of the epiblast that remain (not having migrated through the primitive streak) become the ectoderm (image).

Each of these germ layers will develop into specific structures in the embryo. Whereas the ectoderm and endoderm form tightly connected epithelial sheets, the mesodermal cells are less organized and exist as a loosely connected cell community. The ectoderm gives rise to cell lineages that differentiate to become the central and peripheral nervous systems, sensory organs, epidermis, hair, and nails. Mesodermal cells ultimately become the skeleton, muscles, connective tissue, heart, blood vessels, and kidneys. The endoderm goes on to form the epithelial lining of the gastrointestinal tract, liver, and pancreas, as well as the lungs (image).

During the first several weeks of development, the cells of the endometrium—referred to as decidual cells—nourish the nascent embryo. During prenatal weeks 4–12, the developing placenta gradually takes over the role of feeding the embryo, and the decidual cells are no longer needed. The mature placenta is composed of tissues derived from the embryo, as well as maternal tissues of the endometrium. The placenta connects to the conceptus via the umbilical cord, which carries deoxygenated blood and wastes from the fetus through two umbilical arteries; nutrients and oxygen are carried from the mother to the fetus through the single umbilical vein. The umbilical cord is surrounded by the amnion, and the spaces within the cord around the blood vessels are filled with Wharton’s jelly, a mucous connective tissue.

The maternal portion of the placenta develops from the deepest layer of the endometrium, the decidua basalis. To form the embryonic portion of the placenta, the syncytiotrophoblast and the underlying cells of the trophoblast (cytotrophoblast cells) begin to proliferate along with a layer of extraembryonic mesoderm cells. These form the chorionic membrane, which envelops the entire conceptus as the chorion. The chorionic membrane forms finger-like structures called chorionic villi that burrow into the endometrium like tree roots, making up the fetal portion of the placenta. The cytotrophoblast cells perforate the chorionic villi, burrow farther into the endometrium, and remodel maternal blood vessels to augment maternal blood flow surrounding the villi. Meanwhile, fetal mesenchymal cells derived from the mesoderm fill the villi and differentiate into blood vessels, including the three umbilical blood vessels that connect the embryo to the developing placenta (image).

The placenta develops throughout the embryonic period and during the first several weeks of the fetal period; placentation is complete by weeks 14–16. As a fully developed organ, the placenta provides nutrition and excretion, respiration, and endocrine function (image and image). It receives blood from the fetus through the umbilical arteries. Capillaries in the chorionic villi filter fetal wastes out of the blood and return clean, oxygenated blood to the fetus through the umbilical vein. Nutrients and oxygen are transferred from maternal blood surrounding the villi through the capillaries and into the fetal bloodstream. Some substances move across the placenta by simple diffusion. Oxygen, carbon dioxide, and any other lipid-soluble substances take this route. Other substances move across by facilitated diffusion. This includes water-soluble glucose. The fetus has a high demand for amino acids and iron, and those substances are moved across the placenta by active transport.

Maternal and fetal blood does not commingle because blood cells cannot move across the placenta. This separation prevents the mother’s cytotoxic T cells from reaching and subsequently destroying the fetus, which bears “non-self” antigens. Further, it ensures the fetal red blood cells do not enter the mother’s circulation and trigger antibody development (if they carry “non-self” antigens)—at least until the final stages of pregnancy or birth. This is the reason that, even in the absence of preventive treatment, an Rh− mother doesn’t develop antibodies that could cause hemolytic disease in her first Rh+ fetus.

Although blood cells are not exchanged, the chorionic villi provide ample surface area for the two-way exchange of substances between maternal and fetal blood. The rate of exchange increases throughout gestation as the villi become thinner and increasingly branched. The placenta is permeable to lipid-soluble fetotoxic substances: alcohol, nicotine, barbiturates, antibiotics, certain pathogens, and many other substances that can be dangerous or fatal to the developing embryo or fetus. For these reasons, pregnant women should avoid fetotoxic substances. Alcohol consumption by pregnant women, for example, can result in a range of abnormalities referred to as fetal alcohol spectrum disorders (FASD). These include organ and facial malformations, as well as cognitive and behavioral disorders.

Following gastrulation, rudiments of the central nervous system develop from the ectoderm in the process of neurulation (image). Specialized neuroectodermal tissues along the length of the embryo thicken into the neural plate. During the fourth week, tissues on either side of the plate fold upward into a neural fold. The two folds converge to form the neural tube. The tube lies atop a rod-shaped, mesoderm-derived notochord, which eventually becomes the nucleus pulposus of intervertebral discs. Block-like structures called somites form on either side of the tube, eventually differentiating into the axial skeleton, skeletal muscle, and dermis. During the fourth and fifth weeks, the anterior neural tube dilates and subdivides to form vesicles that will become the brain structures.

Folate, one of the B vitamins, is important to the healthy development of the neural tube. A deficiency of maternal folate in the first weeks of pregnancy can result in neural tube defects, including spina bifida—a birth defect in which spinal tissue protrudes through the newborn’s vertebral column, which has failed to completely close. A more severe neural tube defect is anencephaly, a partial or complete absence of brain tissue.

The embryo, which begins as a flat sheet of cells, begins to acquire a cylindrical shape through the process of embryonic folding (image). The embryo folds laterally and again at either end, forming a C-shape with distinct head and tail ends. The embryo envelops a portion of the yolk sac, which protrudes with the umbilical cord from what will become the abdomen. The folding essentially creates a tube, called the primitive gut, that is lined by the endoderm. The amniotic sac, which was sitting on top of the flat embryo, envelops the embryo as it folds.

Within the first 8 weeks of gestation, a developing embryo establishes the rudimentary structures of all of its organs and tissues from the ectoderm, mesoderm, and endoderm. This process is called organogenesis.

Like the central nervous system, the heart also begins its development in the embryo as a tube-like structure, connected via capillaries to the chorionic villi. Cells of the primitive tube-shaped heart are capable of electrical conduction and contraction. The heart begins beating in the beginning of the fourth week, although it does not actually pump embryonic blood until a week later, when the oversized liver has begun producing red blood cells. (This is a temporary responsibility of the embryonic liver that the bone marrow will assume during fetal development.) During weeks 4–5, the eye pits form, limb buds become apparent, and the rudiments of the pulmonary system are formed.

During the sixth week, uncontrolled fetal limb movements begin to occur. The gastrointestinal system develops too rapidly for the embryonic abdomen to accommodate it, and the intestines temporarily loop into the umbilical cord. Paddle-shaped hands and feet develop fingers and toes by the process of apoptosis (programmed cell death), which causes the tissues between the fingers to disintegrate. By week 7, the facial structure is more complex and includes nostrils, outer ears, and lenses (image). By the eighth week, the head is nearly as large as the rest of the embryo’s body, and all major brain structures are in place. The external genitalia are apparent, but at this point, male and female embryos are indistinguishable. Bone begins to replace cartilage in the embryonic skeleton through the process of ossification. By the end of the embryonic period, the embryo is approximately 3 cm (1.2 in) from crown to rump and weighs approximately 8 g (0.25 oz).

The human heart is the first functional organ to develop. It begins beating and pumping blood around day 21 or 22, a mere three weeks after fertilization. This emphasizes the critical nature of the heart in distributing blood through the vessels and the vital exchange of nutrients, oxygen, and wastes both to and from the developing baby. The critical early development of the heart is reflected by the prominent heart bulge that appears on the anterior surface of the embryo.

The heart forms from an embryonic tissue called mesoderm around 18 to 19 days after fertilization. Mesoderm is one of the three primary germ layers that differentiates early in development that collectively gives rise to all subsequent tissues and organs. The heart begins to develop near the head of the embryo in a region known as the cardiogenic area. Following chemical signals called factors from the underlying endoderm (another of the three primary germ layers), the cardiogenic area begins to form two strands called the cardiogenic cords (image). As the cardiogenic cords develop, a lumen rapidly develops within them. At this point, they are referred to as endocardial tubes. The two tubes migrate together and fuse to form a single primitive heart tube. The primitive heart tube quickly forms five distinct regions. From head to tail, these include the truncus arteriosus, bulbus cordis, primitive ventricle, primitive atrium, and the sinus venosus. Initially, all venous blood flows into the sinus venosus, and contractions propel the blood from tail to head, or from the sinus venosus to the truncus arteriosus. This is a very different pattern from that of an adult.

The five regions of the primitive heart tube develop into recognizable structures in a fully developed heart. The truncus arteriosus will eventually divide and give rise to the ascending aorta and pulmonary trunk. The bulbus cordis develops into the right ventricle. The primitive ventricle forms the left ventricle. The primitive atrium becomes the anterior portions of both the right and left atria, and the two auricles. The sinus venosus develops into the posterior portion of the right atrium, the SA node, and the coronary sinus.

As the primitive heart tube elongates, it begins to fold within the pericardium, eventually forming an S shape, which places the chambers and major vessels into an alignment similar to the adult heart. This process occurs between days 23 and 28. The remainder of the heart development pattern includes development of septa and valves, and remodeling of the actual chambers. Partitioning of the atria and ventricles by the interatrial septum, interventricular septum, and atrioventricular septum is complete by the end of the fifth week, although the fetal blood shunts remain until birth or shortly after. The atrioventricular valves form between weeks five and eight, and the semilunar valves form between weeks five and nine.

Review

The heart is the first organ to form and become functional, emphasizing the importance of transport of material to and from the developing infant. It originates about day 18 or 19 from the mesoderm and begins beating and pumping blood about day 21 or 22. It forms from the cardiogenic region near the head and is visible as a prominent heart bulge on the surface of the embryo. Originally, it consists of a pair of strands called cardiogenic cords that quickly form a hollow lumen and are referred to as endocardial tubes. These then fuse into a single heart tube and differentiate into the truncus arteriosus, bulbus cordis, primitive ventricle, primitive atrium, and sinus venosus, starting about day 22. The primitive heart begins to form an S shape within the pericardium between days 23 and 28. The internal septa begin to form about day 28, separating the heart into the atria and ventricles, although the foramen ovale persists until shortly after birth. Between weeks five and eight, the atrioventricular valves form. The semilunar valves form between weeks five and nine.

The axial skeleton begins to form during early embryonic development. However, growth, remodeling, and ossification (bone formation) continue for several decades after birth before the adult skeleton is fully formed. Knowledge of the developmental processes that give rise to the skeleton is important for understanding the abnormalities that may arise in skeletal structures.

Development of the Skull

During the third week of embryonic development, a rod-like structure called the notochord develops dorsally along the length of the embryo. The tissue overlying the notochord enlarges and forms the neural tube, which will give rise to the brain and spinal cord. By the fourth week, mesoderm tissue located on either side of the notochord thickens and separates into a repeating series of block-like tissue structures, each of which is called a somite. As the somites enlarge, each one will split into several parts. The most medial of these parts is called a sclerotome. The sclerotomes consist of an embryonic tissue called mesenchyme, which will give rise to the fibrous connective tissues, cartilages, and bones of the body.

The bones of the skull arise from mesenchyme during embryonic development in two different ways. The first mechanism produces the bones that form the top and sides of the brain case. This involves the local accumulation of mesenchymal cells at the site of the future bone. These cells then differentiate directly into bone producing cells, which form the skull bones through the process of intramembranous ossification. As the brain case bones grow in the fetal skull, they remain separated from each other by large areas of dense connective tissue, each of which is called a fontanelle (image). The fontanelles are the soft spots on an infant’s head. They are important during birth because these areas allow the skull to change shape as it squeezes through the birth canal. After birth, the fontanelles allow for continued growth and expansion of the skull as the brain enlarges. The largest fontanelle is located on the anterior head, at the junction of the frontal and parietal bones. The fontanelles decrease in size and disappear by age 2. However, the skull bones remained separated from each other at the sutures, which contain dense fibrous connective tissue that unites the adjacent bones. The connective tissue of the sutures allows for continued growth of the skull bones as the brain enlarges during childhood growth.

The second mechanism for bone development in the skull produces the facial bones and floor of the brain case. This also begins with the localized accumulation of mesenchymal cells. However, these cells differentiate into cartilage cells, which produce a hyaline cartilage model of the future bone. As this cartilage model grows, it is gradually converted into bone through the process of endochondral ossification. This is a slow process and the cartilage is not completely converted to bone until the skull achieves its full adult size.

At birth, the brain case and orbits of the skull are disproportionally large compared to the bones of the jaws and lower face. This reflects the relative underdevelopment of the maxilla and mandible, which lack teeth, and the small sizes of the paranasal sinuses and nasal cavity. During early childhood, the mastoid process enlarges, the two halves of the mandible and frontal bone fuse together to form single bones, and the paranasal sinuses enlarge. The jaws also expand as the teeth begin to appear. These changes all contribute to the rapid growth and enlargement of the face during childhood.

Development of the Vertebral Column and Thoracic cage

Development of the vertebrae begins with the accumulation of mesenchyme cells from each sclerotome around the notochord. These cells differentiate into a hyaline cartilage model for each vertebra, which then grow and eventually ossify into bone through the process of endochondral ossification. As the developing vertebrae grow, the notochord largely disappears. However, small areas of notochord tissue persist between the adjacent vertebrae and this contributes to the formation of each intervertebral disc.

The ribs and sternum also develop from mesenchyme. The ribs initially develop as part of the cartilage model for each vertebra, but in the thorax region, the rib portion separates from the vertebra by the eighth week. The cartilage model of the rib then ossifies, except for the anterior portion, which remains as the costal cartilage. The sternum initially forms as paired hyaline cartilage models on either side of the anterior midline, beginning during the fifth week of development. The cartilage models of the ribs become attached to the lateral sides of the developing sternum. Eventually, the two halves of the cartilaginous sternum fuse together along the midline and then ossify into bone. The manubrium and body of the sternum are converted into bone first, with the xiphoid process remaining as cartilage until late in life.

Embryologically, the appendicular skeleton arises from mesenchyme, a type of embryonic tissue that can differentiate into many types of tissues, including bone or muscle tissue. Mesenchyme gives rise to the bones of the upper and lower limbs, as well as to the pectoral and pelvic girdles. Development of the limbs begins near the end of the fourth embryonic week, with the upper limbs appearing first. Thereafter, the development of the upper and lower limbs follows similar patterns, with the lower limbs lagging behind the upper limbs by a few days.

Limb Growth

Each upper and lower limb initially develops as a small bulge called a limb bud, which appears on the lateral side of the early embryo. The upper limb bud appears near the end of the fourth week of development, with the lower limb bud appearing shortly after (image).

Initially, the limb buds consist of a core of mesenchyme covered by a layer of ectoderm. The ectoderm at the end of the limb bud thickens to form a narrow crest called the apical ectodermal ridge. This ridge stimulates the underlying mesenchyme to rapidly proliferate, producing the outgrowth of the developing limb. As the limb bud elongates, cells located farther from the apical ectodermal ridge slow their rates of cell division and begin to differentiate. In this way, the limb develops along a proximal-to-distal axis.

During the sixth week of development, the distal ends of the upper and lower limb buds expand and flatten into a paddle shape. This region will become the hand or foot. The wrist or ankle areas then appear as a constriction that develops at the base of the paddle. Shortly after this, a second constriction on the limb bud appears at the future site of the elbow or knee. Within the paddle, areas of tissue undergo cell death, producing separations between the growing fingers and toes. Also during the sixth week of development, mesenchyme within the limb buds begins to differentiate into hyaline cartilage that will form models of the future limb bones.

The early outgrowth of the upper and lower limb buds initially has the limbs positioned so that the regions that will become the palm of the hand or the bottom of the foot are facing medially toward the body, with the future thumb or big toe both oriented toward the head. During the seventh week of development, the upper limb rotates laterally by 90 degrees, so that the palm of the hand faces anteriorly and the thumb points laterally. In contrast, the lower limb undergoes a 90-degree medial rotation, thus bringing the big toe to the medial side of the foot.

Ossification of Appendicular Bones

All of the girdle and limb bones, except for the clavicle, develop by the process of endochondral ossification. This process begins as the mesenchyme within the limb bud differentiates into hyaline cartilage to form cartilage models for future bones. By the twelfth week, a primary ossification center will have appeared in the diaphysis (shaft) region of the long bones, initiating the process that converts the cartilage model into bone. A secondary ossification center will appear in each epiphysis (expanded end) of these bones at a later time, usually after birth. The primary and secondary ossification centers are separated by the epiphyseal plate, a layer of growing hyaline cartilage. This plate is located between the diaphysis and each epiphysis. It continues to grow and is responsible for the lengthening of the bone. The epiphyseal plate is retained for many years, until the bone reaches its final, adult size, at which time the epiphyseal plate disappears and the epiphysis fuses to the diaphysis. (Seek additional content on ossification in the chapter on bone tissue.)

Small bones, such as the phalanges, will develop only one secondary ossification center and will thus have only a single epiphyseal plate. Large bones, such as the femur, will develop several secondary ossification centers, with an epiphyseal plate associated with each secondary center. Thus, ossification of the femur begins at the end of the seventh week with the appearance of the primary ossification center in the diaphysis, which rapidly expands to ossify the shaft of the bone prior to birth. Secondary ossification centers develop at later times. Ossification of the distal end of the femur, to form the condyles and epicondyles, begins shortly before birth. Secondary ossification centers also appear in the femoral head late in the first year after birth, in the greater trochanter during the fourth year, and in the lesser trochanter between the ages of 9 and 10 years. Once these areas have ossified, their fusion to the diaphysis and the disappearance of each epiphyseal plate follow a reversed sequence. Thus, the lesser trochanter is the first to fuse, doing so at the onset of puberty (around 11 years of age), followed by the greater trochanter approximately 1 year later. The femoral head fuses between the ages of 14–17 years, whereas the distal condyles of the femur are the last to fuse, between the ages of 16–19 years. Knowledge of the age at which different epiphyseal plates disappear is important when interpreting radiographs taken of children. Since the cartilage of an epiphyseal plate is less dense than bone, the plate will appear dark in a radiograph image. Thus, a normal epiphyseal plate may be mistaken for a bone fracture.

The clavicle is the one appendicular skeleton bone that does not develop via endochondral ossification. Instead, the clavicle develops through the process of intramembranous ossification. During this process, mesenchymal cells differentiate directly into bone-producing cells, which produce the clavicle directly, without first making a cartilage model. Because of this early production of bone, the clavicle is the first bone of the body to begin ossification, with ossification centers appearing during the fifth week of development. However, ossification of the clavicle is not complete until age 25.

Review

The bones of the appendicular skeleton arise from embryonic mesenchyme. Limb buds appear at the end of the fourth week. The apical ectodermal ridge, located at the end of the limb bud, stimulates growth and elongation of the limb. During the sixth week, the distal end of the limb bud becomes paddle-shaped, and selective cell death separates the developing fingers and toes. At the same time, mesenchyme within the limb bud begins to differentiate into hyaline cartilage, forming models for future bones. During the seventh week, the upper limbs rotate laterally and the lower limbs rotate medially, bringing the limbs into their final positions.

Endochondral ossification, the process that converts the hyaline cartilage model into bone, begins in most appendicular bones by the twelfth fetal week. This begins as a primary ossification center in the diaphysis, followed by the later appearance of one or more secondary ossifications centers in the regions of the epiphyses. Each secondary ossification center is separated from the primary ossification center by an epiphyseal plate. Continued growth of the epiphyseal plate cartilage provides for bone lengthening. Disappearance of the epiphyseal plate is followed by fusion of the bony components to form a single, adult bone.

The clavicle develops via intramembranous ossification, in which mesenchyme is converted directly into bone tissue. Ossification within the clavicle begins during the fifth week of development and continues until 25 years of age.

Development of the respiratory system begins early in the fetus. It is a complex process that includes many structures, most of which arise from the endoderm. Towards the end of development, the fetus can be observed making breathing movements. Until birth, however, the mother provides all of the oxygen to the fetus as well as removes all of the fetal carbon dioxide via the placenta.

Time Line

The development of the respiratory system begins at about week 4 of gestation. By week 28, enough alveoli have matured that a baby born prematurely at this time can usually breathe on its own. The respiratory system, however, is not fully developed until early childhood, when a full complement of mature alveoli is present.

Weeks 4–7

Respiratory development in the embryo begins around week 4. Ectodermal tissue from the anterior head region invaginates posteriorly to form olfactory pits, which fuse with endodermal tissue of the developing pharynx. An olfactory pit is one of a pair of structures that will enlarge to become the nasal cavity. At about this same time, the lung bud forms. The lung bud is a dome-shaped structure composed of tissue that bulges from the foregut. The foregut is endoderm just inferior to the pharyngeal pouches. The laryngotracheal bud is a structure that forms from the longitudinal extension of the lung bud as development progresses. The portion of this structure nearest the pharynx becomes the trachea, whereas the distal end becomes more bulbous, forming bronchial buds. A bronchial bud is one of a pair of structures that will eventually become the bronchi and all other lower respiratory structures (image).

Weeks 7–16

Bronchial buds continue to branch as development progresses until all of the segmental bronchi have been formed. Beginning around week 13, the lumens of the bronchi begin to expand in diameter. By week 16, respiratory bronchioles form. The fetus now has all major lung structures involved in the airway.

Weeks 16–24

Once the respiratory bronchioles form, further development includes extensive vascularization, or the development of the blood vessels, as well as the formation of alveolar ducts and alveolar precursors. At about week 19, the respiratory bronchioles have formed. In addition, cells lining the respiratory structures begin to differentiate to form type I and type II pneumocytes. Once type II cells have differentiated, they begin to secrete small amounts of pulmonary surfactant. Around week 20, fetal breathing movements may begin.

Weeks 24–Term

Major growth and maturation of the respiratory system occurs from week 24 until term. More alveolar precursors develop, and larger amounts of pulmonary surfactant are produced. Surfactant levels are not generally adequate to create effective lung compliance until about the eighth month of pregnancy. The respiratory system continues to expand, and the surfaces that will form the respiratory membrane develop further. At this point, pulmonary capillaries have formed and continue to expand, creating a large surface area for gas exchange. The major milestone of respiratory development occurs at around week 28, when sufficient alveolar precursors have matured so that a baby born prematurely at this time can usually breathe on its own. However, alveoli continue to develop and mature into childhood. A full complement of functional alveoli does not appear until around 8 years of age.

Fetal “Breathing”

Although the function of fetal breathing movements is not entirely clear, they can be observed starting at 20–21 weeks of development. Fetal breathing movements involve muscle contractions that cause the inhalation of amniotic fluid and exhalation of the same fluid, with pulmonary surfactant and mucus. Fetal breathing movements are not continuous and may include periods of frequent movements and periods of no movements. Maternal factors can influence the frequency of breathing movements. For example, high blood glucose levels, called hyperglycemia, can boost the number of breathing movements. Conversely, low blood glucose levels, called hypoglycemia, can reduce the number of fetal breathing movements. Tobacco use is also known to lower fetal breathing rates. Fetal breathing may help tone the muscles in preparation for breathing movements once the fetus is born. It may also help the alveoli to form and mature. Fetal breathing movements are considered a sign of robust health.

Birth

Prior to birth, the lungs are filled with amniotic fluid, mucus, and surfactant. As the fetus is squeezed through the birth canal, the fetal thoracic cavity is compressed, expelling much of this fluid. Some fluid remains, however, but is rapidly absorbed by the body shortly after birth. The first inhalation occurs within 10 seconds after birth and not only serves as the first inspiration, but also acts to inflate the lungs. Pulmonary surfactant is critical for inflation to occur, as it reduces the surface tension of the alveoli. Preterm birth around 26 weeks frequently results in severe respiratory distress, although with current medical advancements, some babies may survive. Prior to 26 weeks, sufficient pulmonary surfactant is not produced, and the surfaces for gas exchange have not formed adequately; therefore, survival is low.

Review

The development of the respiratory system in the fetus begins at about 4 weeks and continues into childhood. Ectodermal tissue in the anterior portion of the head region invaginates posteriorly, forming olfactory pits, which ultimately fuse with endodermal tissue of the early pharynx. At about this same time, an protrusion of endodermal tissue extends anteriorly from the foregut, producing a lung bud, which continues to elongate until it forms the laryngotracheal bud. The proximal portion of this structure will mature into the trachea, whereas the bulbous end will branch to form two bronchial buds. These buds then branch repeatedly, so that at about week 16, all major airway structures are present. Development progresses after week 16 as respiratory bronchioles and alveolar ducts form, and extensive vascularization occurs. Alveolar type I cells also begin to take shape. Type II pulmonary cells develop and begin to produce small amounts of surfactant. As the fetus grows, the respiratory system continues to expand as more alveoli develop and more surfactant is produced. Beginning at about week 36 and lasting into childhood, alveolar precursors mature to become fully functional alveoli. At birth, compression of the thoracic cavity forces much of the fluid in the lungs to be expelled. The first inhalation inflates the lungs. Fetal breathing movements begin around week 20 or 21, and occur when contractions of the respiratory muscles cause the fetus to inhale and exhale amniotic fluid. These movements continue until birth and may help to tone the muscles in preparation for breathing after birth and are a sign of good health.

The endocrine system arises from all three embryonic germ layers. The endocrine glands that produce the steroid hormones, such as the gonads and adrenal cortex, arise from the mesoderm. In contrast, endocrine glands that arise from the endoderm and ectoderm produce the amine, peptide, and protein hormones. The pituitary gland arises from two distinct areas of the ectoderm: the anterior pituitary gland arises from the oral ectoderm, whereas the posterior pituitary gland arises from the neural ectoderm at the base of the hypothalamus. The pineal gland also arises from the ectoderm. The two structures of the adrenal glands arise from two different germ layers: the adrenal cortex from the mesoderm and the adrenal medulla from ectoderm neural cells. The endoderm gives rise to the thyroid and parathyroid glands, as well as the pancreas and the thymus.

As the body ages, changes occur that affect the endocrine system, sometimes altering the production, secretion, and catabolism of hormones. For example, the structure of the anterior pituitary gland changes as vascularization decreases and the connective tissue content increases with increasing age. This restructuring affects the gland’s hormone production. For example, the amount of human growth hormone that is produced declines with age, resulting in the reduced muscle mass commonly observed in the elderly.

The adrenal glands also undergo changes as the body ages; as fibrous tissue increases, the production of cortisol and aldosterone decreases. Interestingly, the production and secretion of epinephrine and norepinephrine remain normal throughout the aging process.

A well-known example of the aging process affecting an endocrine gland is menopause and the decline of ovarian function. With increasing age, the ovaries decrease in both size and weight and become progressively less sensitive to gonadotropins. This gradually causes a decrease in estrogen and progesterone levels, leading to menopause and the inability to reproduce. Low levels of estrogens and progesterone are also associated with some disease states, such as osteoporosis, atherosclerosis, and hyperlipidemia, or abnormal blood lipid levels.

Testosterone levels also decline with age, a condition called andropause (or viropause); however, this decline is much less dramatic than the decline of estrogens in women, and much more gradual, rarely affecting sperm production until very old age. Although this means that males maintain their ability to father children for decades longer than females, the quantity, quality, and motility of their sperm is often reduced.

As the body ages, the thyroid gland produces less of the thyroid hormones, causing a gradual decrease in the basal metabolic rate. The lower metabolic rate reduces the production of body heat and increases levels of body fat. Parathyroid hormones, on the other hand, increase with age. This may be because of reduced dietary calcium levels, causing a compensatory increase in parathyroid hormone. However, increased parathyroid hormone levels combined with decreased levels of calcitonin (and estrogens in women) can lead to osteoporosis as PTH stimulates demineralization of bones to increase blood calcium levels. Notice that osteoporosis is common in both elderly males and females.

Increasing age also affects glucose metabolism, as blood glucose levels spike more rapidly and take longer to return to normal in the elderly. In addition, increasing glucose intolerance may occur because of a gradual decline in cellular insulin sensitivity. Almost 27 percent of Americans aged 65 and older have diabetes.

Review

The endocrine system originates from all three germ layers of the embryo, including the endoderm, ectoderm, and mesoderm. In general, different hormone classes arise from distinct germ layers. Aging affects the endocrine glands, potentially affecting hormone production and secretion, and can cause disease. The production of hormones, such as human growth hormone, cortisol, aldosterone, sex hormones, and the thyroid hormones, decreases with age.

In approximately nine months, a single cell—a fertilized egg—develops into a fully formed infant consisting of trillions of cells with myriad specialized functions. The dramatic changes of fertilization, embryonic development, and fetal development are followed by remarkable adaptations of the newborn to life outside the womb. An offspring’s normal development depends upon the appropriate synthesis of structural and functional proteins. This, in turn, is governed by the genetic material inherited from the parental egg and sperm, as well as environmental factors.