Chapter 28: Human Development
Chapter 28: Human Developmentby John F. Neas
The period of prenatal development can be subdivided into preembryonic, embryonic, and fetal periods. The preembryonic period begins with the fertilization of a secondary oocyte and continues through cleavage (an initial series of cells divisions) and implantation (the movement of the preembryo into the uterine lining). The preembryonic period is followed by the embryonic period that extends from implantation, typically occurring on the ninth or tenth day after fertilization, and continuing to the end of the eighth developmental week during which time the organ systems develop. The fetal period begins at the start of the ninth developmental week and culminates in parturition, or birth.
The first two weeks of development, the preembryonic stage, is a period of cell division and differentiation. The events of this stage include fertilization, transportation of the zygote through the uterine tube, mitotic cell divisions (cleavage), formation of embryonic tissue and extraembryonic membranes (amnion, chorion, allantois, placenta, and umbilical cord), and the beginning of implantation of the blastocyst into the uterine wall. The term conceptus refers to all the products of conception including all structures that develop from the fertilized ovum (zygote), including the embryo and its extraembryonic membranes. The developing conceptus during the preembryonic period is self-sustaining. The embryo, however, is not self-supporting and must derive sustenance and protection from the mother through the extraembryonic membranes.
Preembryonic forms are the zygote (fertilized egg), morula (a solid ball of cells), blastocyst (hollow ball with a single germ layer), and bilaminar embryonic disc (with two germ layers).
First Week—Fertilization, Cleavage, Blastulation
The term fertilization refers to the penetration of an ovum by a spermatozoon and the subsequent fusion of the haploid gametes (sperm and eggs have 23 chromosomes in human beings) into a diploid zygote with the normal somatic number of chromosomes (46 in human beings).
The spermatozoon and ovum have very different functional roles and contributions. The spermatozoon merely delivers paternal chromosomes to the site of fertilization, but the ovum provides all the nourishment and genetic programming to support embryonic development for almost a week after conception. The volume of the ovum, therefore, is much greater than that of the spermatozoon.
Fertilization normally occurs in the ampulla of the uterine (Fallopian) tube and usually within 24 hours after ovulation. Peristaltic contractions and ciliary action transport the secondary oocyte a few centimeters through the uterine tube. The spermatozoa, however, must travel the distance between the vagina and the fertilization site in the ampulla. Transit time for the spermatozoa may be from 30 minutes to 2 hours. Several factors apparently accelerate the movement of spermatozoa in their passage. Sperm probably swim up the female reproductive tract by using whip-like movements of their flagella. In addition, the acrosome of sperm produces an enzyme called acrosin that stimulates sperm motility and migration within the female reproductive tract. Finally, contractions of the uterine musculature and ciliary currents in the uterine tubes probably help transport the sperm.
During coitus (sexual intercourse), a male ejaculates between 100 million and 500 million sperm into the vagina (typically about 200 million). This tremendous number is needed because of the high rate of sperm fatality. Very few, perhaps only several hundred to several thousand, enter the uterine tube and fewer than 100 survive to reach the ampulla. Therefore, males are functionally sterile if they have a sperm count below 20 million/ml because too few spermatozoa survive to reach the secondary oocyte. One or two spermatozoa cannot complete fertilization because of the condition of the secondary oocyte at ovulation.
Secondary Oocyte at Ovulation
A woman usually ovulates one secondary oocyte each month, totaling about four hundred during her reproductive years. Ovulation occurs before completion of oocyte maturation, and the secondary oocyte that leaves the follicle is arrested in metaphase of the second meiotic division during which time metabolism has been discontinued. To develop further, the secondary oocyte must await stimulation by fertilization.
Fertilization is complicated by the fact that the ovulated secondary oocyte is surrounded by intercellular materials, including a thin transparent gelatinous layer of protein and polysaccharides called the zona pellucida and several layers of cells called the corona radiata, the innermost of which are follicle (granulosa) cells. The corona radiata protects the secondary oocyte as it passes through the ruptured follicular wall and into the infundibulum of the uterine tube. The process of fertilization requires only a single sperm to contact the oocyte membrane, but that spermatozoon must first penetrate the corona radiata.
Besides assisting in the transport of sperm, the female reproductive tract also confers on sperm the capacity to fertilize a secondary oocyte. Sperm undergo maturation in the epididymis and are motile upon arrival in the vagina. Experiments have shown, however, that freshly ejaculated sperm are infertile and must remain in the acidic environment of the female reproductive tract for at least seven hours before they gain the ability to fertilize a secondary oocyte. The functional changes that sperm undergo in the female reproductive tract that enable them to fertilize a secondary oocyte are known as capacitation. The sperm cell has an organelle called an acrosome that forms a cap over the head. Capacitation is not fully understood but, during this process, the acrosome presumably secretes a trypsin-like enzyme that digests protein (proteinase) and hyaluronidase that digests hyaluronic acid, which is an important constituent of connective tissue
When a sperm encounters a secondary oocyte in the uterine tube, an acrosomal reaction occurs that exposes the digestive enzymes of the acrosome and allows a sperm to penetrate the corona radiata and zona pellucida. Dozens of spermatozoa must release hyaluronidase before the intercellular cement between the follicular cells in the corona radiata break down sufficiently to permit fertilization.
Oocyte Activation; Prevention of Polyspermy
Regardless of how many spermatozoa make their way through the zona pellucida and corona radiata, only a single spermatozoon will accomplish fertilization and activate the oocyte.
As the first sperm penetrates the zona pellucida and contacts the secondary oocyte, the plasma membranes of the gametes fuse, and the sperm enters the ooplasm, or cytoplasm of the oocyte. When the cell membranes of the sperm and secondary oocyte merge, the secondary oocyte becomes an ovum. The process of membrane fusion triggers oocyte activation—a series of changes in the metabolic activity of the secondary oocyte, including a sudden rise in metabolic rate. Furthermore, the cell membrane of the oocyte undergoes immediate electrical changes that block the entry of other sperm, and enzymes produced by the fertilized ovum alter receptor sites so that sperm already bound are detached and others are prevented from binding. Therefore, only one sperm can fertilize a secondary oocyte. Normal development cannot occur if more than one sperm penetrates the oocyte membrane, an event called polyspermy.
Completion of Meiosis
The fertilization of a secondary oocyte by a sperm in the uterine tube stimulates the ovum to complete its second meiotic division and form a diploid zygote. Like the first meiotic division, the second produces a large mature ovum that contains all the cytoplasm and the second polar body that, like the first polar body, ultimately fragments and disintegrates.
Pronucleus Formation and Amphimixis
At fertilization, the entire sperm enters the cytoplasm of the much larger ovum, the tail is shed, and the nucleus in the head develops into a structure called the male pronucleus. After oocyte activation and completion of meiosis, the nuclear material remaining within the ovum reorganizes as the female pronucleus. The male pronucleus migrates toward the center of the cell, and the two pronuclei fuse in a process called amphimixis to produce a segmentation nucleus that contains 23 chromosomes from the male pronucleus and 23 chromosomes from the female pronucleus. Within twelve hours, the nuclear membrane in the ovum disappears, and the haploid number of chromosomes (23) in the ovum joins the haploid number of chromosomes from the sperm. Thus, a fertilized egg, or zygote, is formed that contains the diploid number of chromosomes (46). The fertilized ovum, or zygote, consisting of a segmentation nucleus, cytoplasm, and enveloping membrane, prepares to begin mitotic divisions called cleavage that will ultimately produce billions of specialized cells.
A secondary oocyte that is ovulated but not fertilized does not complete its second meiotic division. Rather, it disintegrates twelve to twenty-four hours after ovulation without completing meiosis. Therefore, fertilization cannot occur if intercourse occurs beyond one day following ovulation. Sperm, however, can survive up to three days in the female reproductive tract. Thus, fertilization can occur if coitus occurs within three days before the day of ovulation.
Fertilization initiates cleavage, a series of rapid mitotic divisions that subdivides the cytoplasm of the zygote into smaller, essentially equipotential cells called blastomeres contained by the zona pellucida. Cleavage generates a multicellular system essential for further differentiation and morphogenesis. Cleavage increases the number of cells, but it does not result in an increase in the size of the developing organism. Cleavage begins immediately after fertilization and ends when the developing structure first contacts the uterine wall. During the period of cleavage, the zygote becomes a preembryo that develops into a multicellular complex called a blastocyst.
The first cleavage division results in the formation of a preembryo consisting of two identical blastomeres. The first cleavage is completed approximately 30 hours after fertilization, and each succeeding division takes slightly less time, occurring at 10- to 12-hour intervals. All of the blastomeres undergo mitosis simultaneously during the initial cleavage divisions, but the timing becomes less predictable as the number of blastomeres increases. The second cleavage is completed by the second day after conception. There are 16 blastomeres by the end of the third day.
Several cleavage divisions occur as the structure moves down the uterine tube toward the uterus. By the third day, successive divisions increase the number of blastomeres to about sixteen, forming a solid ball called a morula ("mulberry") consisting of an inner and an outer cell mass. The morula has the first evident segregation of materials and potencies. The morula enters the uterus on the third or fourth day. The morula has undergone several mitotic divisions, but it is about the same size as the original zygote because additional nutrients necessary for growth have not entered the cells.
Blastocyst Formation (Blastulation)
As the number of cells increases, the structure moves from the original site of fertilization down through the ciliated uterine tube toward the uterus and enters the uterine cavity on about the third day. The developing structure remains unattached in the uterine cavity for about three days during which time the center of the morula fills with fluid passing in from the uterine cavity. The fluid-filled spaces that form between the blastomeres of the morula coalesce by the fourth or fifth day into a large blastocyst cavity (blastocoel, or primary yolk sac). The morula is now a blastocyst. The blastocyst cavity separates a single spherical outer layer of trophoblast cells (trophectoderm) that form the wall of the blastocyst from a small, inner aggregation of cells called the inner cell mass, or embryoblast, that will become the embryo proper. The trophoblast will later combine with mesoderm to form the chorion that will become the fetal portion of the placenta.
The relatively independent conceptus floats freely in endometrial gland secretions as it passes down the uterine tubes into the uterus where it implants between the fifth and ninth days after ovulation.
The inner cell mass has little visible organization in the early blastocyst stage. At seven days, the conceptus is a blastocyst that enlarges, loses its zona pellucida and, during the following four days, becomes implanted in the uterine mucosa. During those four days, the inner cell mass begins to separate from the trophoblast. The separation gradually increases, producing a fluid-filled chamber called the amniotic cavity. At this stage the cells of the inner cell mass are organized into an oval sheet called a bilaminar embryonic disc (blastodisc) that initially consists of two epithelial layers—the epiblast (ectoderm) facing the amniotic cavity and the hypoblast (endoderm) exposed to the fluid contents of the blastocoel.
The trophoblast differentiates from the superficial layer of cells of the morula. The trophoblast differentiates into an actively invading, superficial layer, the syncytiotrophoblast, and a deep stratum, the cytotrophoblast. The cytotrophoblast and syncytiotrophoblast form the chorion and ultimately the definitive placenta. Cytotrophoblast also produces mesoblast that forms extraembryonic blood vessels.
Splanchnic mesoderm (lateral plate, hypomere) and hindgut endoderm produce the yolk sac and allantois. Splanchnic mesoderm also produces mesoderm of the amnion, the lining of which develops from surface ectoderm
It takes about 4 days after fertilization for the zygote to reach the uterus. The zygote arrives in the uterine cavity as a morula, and over the next 23 days, blastocyst (blastula) formation occurs. The blastocyst remains free within the uterine cavity for 24 days before it attaches to the uterine wall. During this period, the cells absorb nutrients rich in glycogen from secretions of the endometrial glands sometimes called uterine milk.
The process of implantation, or nidation, begins between the seventh and eighth days after fertilization. Implantation begins with the attachment of the blastocyst to the endometrium and continues as the blastocyst invades the uterine wall. As implantation proceeds, several other important events occur that set the stage for the formation of vital embryonic structures.
Implantation begins as the surface of the blastocyst closest to the inner cell contacts and adheres to the endometrial lining, usually upon the posterior wall of the fundus or body of the uterus. The endometrium at this time is in its postovulatory phase. The trophoblast (trophectoderm) below the implanting blastocyst divides rapidly, producing several layers of cells. Near the endometrial wall, the cell membranes that separate the trophoblast cells disappear, forming a layer of cytoplasm called the syncytiotrophoblast that contains multiple nuclei (Day 8). This outer layer begins to secrete the proteolytic enzyme hyaluronidase that digests and liquefies the intercellular cement between adjacent endometrial cells. The action of the enzyme erodes a gap and depression in the uterine epithelium that enables the blastocyst to penetrate the uterine lining. The migration and division of nearby endometrial cells soon repair the surface and cover the defect. When the repairs are completed, the blastocyst loses contact with the uterine cavity and becomes completely embedded within the endometrium. The blastocyst becomes oriented with the inner cell mass toward the endometrium. Subsequent development occurs entirely within the functional zone of the endometrium.
As implantation progresses, the syncytiotrophoblast continues to enlarge and expand into the surrounding endometrium (Day 9), resulting in disruption and enzymatic digestion of uterine glands. The nutrients released are absorbed by the syncytiotrophoblast and distributed by diffusion across the underlying cytotrophoblast to the inner cell mass. The fluid and nutrients provide the additional nourishment needed to support the early stages of embryo formation, especially during the first week after implantation. Trophoblastic extensions grow around endometrial capillaries and, as the capillary walls are destroyed, maternal blood begins to percolate through trophoblastic channels called lacunae. Finger-like projections called primary villi extend from the trophoblast into the surrounding endometrium. Each primary villus consists of an extension of syncytiotrophoblast with a core of cytotrophoblast. Over the next few days, the trophoblast begins to break down larger endometrial veins and arteries, and blood flow through the lacunae increases. Nutrients are eventually delivered through the placenta for the growth and development of the embryo and fetus.