First week: Migration through the Fallopian Tube
Stage 1: Fertilization
The embryonic development immediately begins upon the fusion of egg and sperm cell. This so-called fertilization occurs as the male sperm enters the corona radiata of the female egg cell and subsequently makes its way through the zona pellucida with the help of enzymatic reactions. It attaches to the surface of the oocyte with its head.
However, this penetration by the sperm cannot be considered as fertilization in the narrower sense, as the egg cell is not yet ready for fertilization at this stage. Yet, the penetration and the attachment of the sperm initiate a number of reactions in the egg cell finally causing the so-called female pronucleus out of its nucleus. At the same time, the head of the sperm swells up to become the male pronucleus. Only now, the cellular and genetic requirements for fertilization are present.
In the egg cell, the two pronuclei move towards each other, fuse, and form the so-called zygote – a diploid cell with 46 chromosomes. From this moment forward, new life develops.
Stage 2: Cleavage
As the fertilization occurs in the fallopian tube but the fertilized egg cell has to nest in the uterus for further development, the activated zygote now has to migrate some distance in the so-called migration through the fallopian tube. During this, it starts to quickly divide several times. As this process is visible as grooves under the microscope, it is referred to as cleavage.
30 hours after fertilization, the first division of the zygote into two daughter cells occurs, which are also referred to as blastomeres. After three days, there are already 16 blastomeres which look like a mulberry in their spherical arrangement. This is why the zygote is also referred to as morula (Latin: morus = mulberry) at this stage.
Stage 3: Blastocyst Formation
While the morula is a single connected cluster of cells, it divides into two separate cell clusters from the fourth day on, an outer cell layer (trophoblast) and an inner cell mass (embryoblast). In addition, a central hollow cavity forms, the so-called blastocyst cavity. It gives the morula space to become the blastocyst. Once this has happened, a blastocyst, surrounded by the trophoblast, has formed after four days. The blastocyst’s embryoblasts in the inner wall already have the foundation for all of the embryo’s tissues and organs.
As the zygote is still surrounded by the zona pellucida at this stage, the above mentioned process of division and differentiation is not accompanied by spatial growth, but it is rather an increase in cells. Once the morula has reached the uterus and has become the blastocyst, the latter actively dissolves the zona pellucida and quickly grows. Fed by uterine glands, the so-called free blastocyst remains in the uterus lumen for two days to finally attach itself to the epithelial tissue of the uterus mucosa on the fifth and sixth day. The attachment begins.
Stage 4: Attachment of the Blastocyst at the Mucosa
Once the free blastocyst has dissolved its zona pellucida and the uterine mucosa has entered the secretion stage, the requirements for the contact and the implantation, which occurs in the second week, are present. During the process of the trophoblast growing into the epithelial tissue of the uterine endometrium, two new cell layers form: the cytotrophoblast and the syncytiotrophoblast. The latter cell layer penetrates the uterine mucosa up to its stroma, resulting in superficial implantation.
Cleavage: mitotic divisions of the zygote leading to the formation of blastomeres.
Morula: cluster of cells with mulberry-like surface formed via the cleavage of the zygote.
Blastocyst: emerges from the morula. Toward the outside, the blastocyst is bordered by the trophoblast, toward the inside; cells of the embryoblast surround the centrally located cavity.
Second week: Implantation
Stage 5: Trophoblast and Embryoblast
The complete implantation of the blastocyst into the uterine mucosa takes slightly less than a week. After the syncytiotrophoblast penetrates the stroma of the uterus, the stroma cells of the surrounding endometrial tissue become decidual cells as they grow and absorb glycogen and fats (decidual reaction), but, even inside the zygote itself, bigger changes take place. From approximately the eighth day on, the bilaminar embryonic disc and the amniotic cavity form. The embryonic disc forms via a conversion process of the embryoblast, during which, the present cells divide into the endoderm and the ectoderm.
This development process is accompanied by a restructuring of the cell clusters, whereby the cells of the emerging ectoderm merge to become a multi-row, columnar epithelium. Based on this, the formation of the amniotic cavity begins, whose inner wall is lined by so-called amnioblasts, which, in turn, grow in from the edges of the ectodermal disc. Thus, the amnion is an ectodermal structure.
While the amnion originates from the edges of the ectoderm, the formation of the primary yolk sac occurs from the edges of the endoderm. For this, endodermal cells of the bilaminar embryonic disc migrate to line the blastocyst cavity.
While the embryoblast differentiates into ectoderm and endoderm and thus allows the formation of the amniotic cavity and the yolk sac, the syncytiotrophoblast further penetrates into the mucosa, and forms capillary connections with it as well as lacunae. These lacunae can incorporate uterine secretion to ensure the supply of the emerging embryonic disc; thus, the foundation is laid for the uteroplacental circulation.
12 days after fertilization, the germ cell is completely implanted in the uterine mucosa. Only a small protrusion in the epithelial tissue of the endometrium that covers it indicates its presence under the microscope.
Bilaminar germinal disc: develops during the course of the conversion processes of the embryoblast, during which the present cells divide into endoderm and ectoderm.
Third week: Trilaminar Embryonic Disc
The beginning of the third week simultaneously marks the beginning of the embryonic period in the narrower sense, which covers a period of approximately five weeks and is completed by the end of the eighth week. A number of conversion and reorganization processes now occur simultaneously, or are based on each other. They lead to a fundamental change in the shape of the germ: away from a round, flat disc to an elongated pear shape.
Stage 6: Conversion of the Primary into the Secondary Yolk Sac
First, the third week is characterized by a reorganization of the present embryonic cavities, whereby the primary yolk sac bursts due to the increasing expansion of the trophoblast (yolk sac burst) and, thus, shrinks to the so-called secondary yolk sac. With its chorionic mesoderm and the developing chorionic villi, the chorionic cavity organizes around the secondary yolk sac. In the following process of embryonic development, the chorionic villi will form the placenta (placenta villous), along with the decidua basalis.
The most important conversion process in this stage of the development is the so-called gastrulation, which is the reshaping of the bilaminar embryonic disc into the trilaminar embryonic disc.
The gastrulation begins around the fourteenth day with the formation of the so-called primitive streak. As a compaction of cells, this primitive streak emerges in the dorsal caudal section of the germinal disc and elongates cranially via cell proliferation. This direction of development does not occur coincidentally, as the directed formation of the primitive streak permanently determines the body axes of the developing embryo. From here on out, body dependent definitions like ‘cranial’ or ‘caudal’ actually make sense.
In addition, the development of the so-called intraembryonic mesoderm occurs originating from the primitive streak. This mesoderm forms the third germ disc. The forming of this germ disc is of significant importance for the further development of the embryo as it forms the mesoblastic cells (mesenchyme cells), which have the ability to differentiate themselves into different sub-cell types in order to build the supporting connective tissue (mesenchyme) of the embryo.
Stage 7: Development of the Chordal Furrow of the Chorda Dorsalis
Also originating from the primitive streak, the so-called chordal furrow develops around the sixteenth day, which is a stripe-shaped structure that grows into the space between ectoderm and endoderm. The chorda dorsalis develops from it, which is another median cell cord. Later on, the spine develops around it.
Stage 8: Formation of the Axial Canal from the Primitive Pit
Aside from its central significance for the development of the spine, the primitive streak also plays a role in the creation of the cell structures, which will later connect the neural canal and the intestinal tract. The primitive pit, which belongs to the primitive streak, continues as a deepening into the chordal furrow and thus forms the so-called axial canal, which opens into the secondary yolk sac. This canal is also referred to as the neurenteric canal as it will connect the later developing neural canal with the intestinal tract, which also develops at a later time.
Stage 9: Neurulation
The last important developmental process in the third embryonic week is the so-called neurulation, which occurs simultaneously with the formation of the chorda dorsalis and begins with a thickening of the ectoderm toward the so-called neural plate. The central nervous system will later develop from this plate.
Around the eighteenth day, the neural plate has reached the size at which it unfolds and forms structures like the neural folds and the neural groove. The neural plate does not exist for long as the so-called neural tube is formed via fusion, which initially is open cranially and caudally. Later on, in the fourth week, it closes. Only upon this closure, neurulation is completed.
Furthermore, the formation of the neural crest should be mentioned in this context. It occurs upon the development of the neural tube, is located in its immediate proximity, and is, among others, responsible for the later development of the spinal ganglia and the ganglia of the autonomic nervous system.
Further Developments at the End of the Third Week
Beside the aforementioned development processes, more changes take place, which lay the foundation for later differentiations. From the twentieth day on, for instance, the paired, so-called somites form. They are cubical structures from which a large part of the axial skeleton, its musculature, and the connective skin tissue will develop.
Furthermore, the intraembryonic coelom develops within the lateral plate mesoderm and the mesoderm. This coelom is a hoof-shaped, paired cavity, which expands caudally from the head area. During the second month, important structures like the pericardial cavity, the pleural cavity, and peritoneal cavity will develop from it.
Also during the third week, the development of the embryonic blood and vessel systems take place. In the meantime, fed by maternal blood via diffusion processes, the embryo forms his first vessels from mesenchyme cells, which were converted into angioblasts, between day 13 and 15. The cells connect to each other and form a network, which increases in density and size due to constant further sprouting. Within this network, two vessels already exist at the end of the third week, which, not only connect with each other, but even fuse. They are the two primitive heart tubes, which form the primitive heart tube through their fusion. Blood begins to circulate, and the heart begins to beat; thus, the circulatory system is the first functioning organ system of the embryo.
Chorionic villi: villi, which develop from the third week of pregnancy on and form the placenta together with the decidua basalis.
Primitive streak: cell agglomeration in the dorsal caudal section of the embryonic disc with primitive knot and primitive pit.
Gastrulation: conversion of the bilaminal embryonic disc into the trilaminar embryonic disc.
Notochord: a cell structure emerging from the chordal furrow around which the spine will develop. It degenerates where it is surrounded by vertebrae, but remains intact in the area of the nucleus pulposus of the intervertebral discs.
Somites: cubical structure from which a major part of the axial skeleton, its muscles, and the connective skin tissue develops
Pathology of Pre-Embryology
It has been verified that approximately 15% of all zygotes perish via abortion. One should assume, however, that the number of zygotes perishing in the first week of pregnancy is much greater than 15%, which might already be explained by the fact that especially the first week after fertilization represents an extremely critical period in embryonic development. Its success is tied to a large number of conditions, such as a sufficient production of progesterone and estrogen, or chromosomal abnormalities of the zygote.
If a pregnant woman without rubella antibodies is infected with rubella during the first three to four months, the principally harmless rubella can lead to severe disturbances in ontogenesis of the embryo. In the first month of pregnancy, the risk for embryopathy after an infection is approximately 60 %. Possible consequences are summarized in the so-called Gregg’s syndrome, which consists of the triad cataract, deafness, and cardiac defect.
Regularly increased alcohol consumption during the first months of pregnancy can result in severe developmental disorders of the embryo. Among others, clinical signs suggesting alcohol embryopathy are: microcephaly, statomotorical and mental retardation, muscle hypotension, and a shortened nasal bridge. Approximately one in every 200 newborns is affected.
Double formation is an embryonic development disorder causing the initial embryonic entity to double. As a consequence, a partial separation of the two embryos occurs so that they remain connected with each other and potentially even share organs. The best-known form of this double formation is the phenomenon of Siamese twins.
Mosaicism describes the manifestation of cell lines with different numbers of chromosomes. It is caused by a non-separation of chromosomes in the anaphase during cleavage (Stage 2). This genetic anomaly can be found in approximately one percent of Down Syndrome patients, who, consequently, not only have cells with 47 chromosomes, but also cells with 46 chromosomes.
At hydatidiform mole, a malformation of the chorionic villi of the placenta is present. The cause is a flawed germ anlage, which leads to a pathological proliferation of the trophoblast. The placental villi develop into grape-shaped vesicles and invade, as such, the maternal myometrium. Here, the risk for metastasis exists (destructive hydatidiform mole). Clinically, a bloody, watery discharge with vesicles can be seen. In relation to the physiological size according to the respective week of pregnancy, the uterus presents as too large. Hydatidiform mole is treated with cytostatics.
Congenital Malformations of the Central Nervous System
This means the disturbance of neurulation during the third and fourth embryonic week caused by, for instance, teratogenic medications. They can lead to severe malformations of the brain and the spinal cord, i.e. the closure of the neural tube at the end of neurulation does not take place, leading to the degeneration of the therefore exposed nervous tissue. If this happens in the head area, this is referred to as anencephaly.