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Fertilization

Image : “Sperm Egg Fertilization” by
TBIT. License: CC0


First week: Migration Through the Fallopian Tube

Stage 1: Fertilization

Sperm egg

Embryonic development immediately begins with the fusion of the egg and sperm cells. This fertilization occurs as the sperm enters the corona radiata of the 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 ready for fertilization at this stage. Yet, the penetration and attachment of the sperm initiate a number of reactions in the egg cell finally causing the female pronucleus out of its nucleus. At the same time, the head of the sperm swells up to become the male pronucleus. Only at this point are the cellular and genetic requirements for fertilization present.

In the egg cell, the 2 pronuclei move towards each other, fuse, and form the zygote – a diploid cell with 46 chromosomes. From this moment forward, new life develops.

Fertilization

Picture: ‘Fertilization’ by BruceBlaus. License: CC BY 3.0

Stage 2: Cleavage

Fertilization occurs in the fallopian tube but the fertilized egg cell has to nest in the uterus for further development. As such, the activated zygote now has to migrate some distance through the fallopian tube. During this migration, the zygote starts to quickly divide several times. As this process is visible as grooves under the microscope, it is referred to as cleavage.

Thirty hours after fertilization, the first division of the zygote into 2 daughter cells occurs. Тhese cells are also referred to as blastomeres. After 3 days, there are already 16 blastomeres that look like a mulberry in their spherical arrangement. This is why the zygote is also referred to as a morula (Latin: morus = mulberry) at this stage.

Pre-Embryonic Cleavages

Picture: ‘Pre-Embryonic Cleavages’ by Phil Schatz. License: CC BY 4.0

Stage 3: Blastocyst formation

Blastocyst day 5

While the morula is a single connected cluster of cells, it divides into 2 separate cell clusters from the 4th day: an outer cell layer (trophoblast) and an inner cell mass (embryoblast). In addition, a central hollow cavity forms, the blastocyst cavity. It gives the morula space to become the blastocyst. Once this has happened, a blastocyst, surrounded by the trophoblast, has formed after 4 days. The blastocyst has 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 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 free blastocyst remains in the uterus lumen for 2 days to finally attach itself to the epithelial tissue of the uterine mucosa on the 5th and 6th day. The attachment then begins.

Stage 4: Attachment of the blastocyst to 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 implantation, which occur in the second week, are present. During the process of the trophoblast growing into the epithelial tissue of the uterine endometrium, 2 new cell layers form the cytotrophoblast and syncytiotrophoblast. The latter cell layer penetrates the uterine mucosa up to its stroma, resulting in superficial implantation.

 

Implantation

Picture: ‘Implantation’ by Phil Schatz. License: CC BY 4.0

Note:

Cleavage: mitotic divisions of the zygote leading to the formation of blastomeres

Morula: cluster of cells with a 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

Development of the Embryonic Disc

Picture: “Development of the Embryonic Disc” by Phil Schatz. License: CC BY 4.0

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, more notable changes take place. From approximately the 8th day, the bilaminar embryonic disc and the amniotic cavity form. The embryonic disc is formed via a conversion process of the embryoblast, during which, the present cells divide into the endoderm and 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. With this, the formation of the amniotic cavity begins, whose inner wall is lined by 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 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.

Twelve 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.

Endometriosis

Picture: ‘Endometriosis’ by BruceBlaus. License: CC BY 3.0

Note:
Bilaminar germinal disc: develops during the course of the conversion processes of the embryoblast, during which the present cells divide into the endoderm and ectoderm.

Pre-Embryonic Development

Picture: ‘Pre-Embryonic Development’ by Phil Schatz. License: CC BY 4.0

Third Week: Trilaminar Embryonic Disc

The beginning of the 3rd week simultaneously marks the beginning of the embryonic period in the narrower sense, which covers a period of approximately 5 weeks and is completed by the end of the 8th 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 yolk sac into the secondary yolk sac

First, the 3rd week is characterized by a reorganization of the present embryonic cavities, in which the primary yolk sac bursts due to the increasing expansion of the trophoblast (yolk sac burst) and, thus, shrinks to the 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.

Cross-Section of the Placenta

Picture: ‘Cross-Section of the Placenta’ by Phil Schatz. License: CC BY 4.0

The most important conversion process in this stage of development is gastrulation, which is the reshaping of the bilaminar embryonic disc into the trilaminar embryonic disc.

Gastrulation begins around the 14th day with the formation of the primitive streak. As cell compaction occurs, 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, body dependent definitions like ‘cranial’ or ‘caudal’ become reasonable.

In addition, the development of the intraembryonic mesoderm occurs, originating from the primitive streak. This mesoderm forms the 3rd germ disc. The forming of this germ disc is important for the further development of the embryo as it forms the mesoblastic cells (mesenchyme cells), which have the ability to differentiate 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 chordal furrow develops around the 16th day, and is a stripe-shaped structure that grows into the space between the ectoderm and endoderm. The chorda dorsalis (notochord) 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 that later connect the neural canal and intestinal tract. The primitive pit, which belongs to the primitive streak, continues as a deepening into the chordal furrow and thus forms the axial canal, which opens into the secondary yolk sac. This canal is also referred to as the neurenteric canal as it will connect the neural canal with the intestinal tract, both of which develop at a later time.

Stage 9: Neurulation

The last important developmental process in the 3rd embryonic week is neurulation, which occurs simultaneously with the formation of the chorda dorsalis and begins with a thickening of the ectoderm toward the neural plate. The central nervous system later develops from this plate.

Around the 18th day, the neural plate has reached the size at which it unfolds and forms structures like the neural folds and neural groove. The neural plate does not exist for long as the neural tube is formed via fusion, which initially is open cranially and caudally. Later on, in the 4th 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 with the development of the neural tube, is located in its immediate proximity, and plays a role in the development of the spinal ganglia and ganglia of the autonomic nervous system.

Neurulation

Picture: ‘Neurulation’ by Phil Schatz. License: CC BY 4.0

Further Developments at the end of the third week

Besides the aforementioned development processes, more changes take place, which lay the foundation for later differentiations. From the 20th day, for instance, the paired somites form. They are cubical structures from which a large part of the axial skeleton, its musculature, and 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 that expands caudally from the head area. During the second month, important structures like the pericardial cavity, pleural cavity, and peritoneal cavity will develop from it.

Further, during the 3rd week, the development of the embryonic blood and vessel systems takes place. In the meantime, fed by maternal blood via diffusion processes, the embryo forms its 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 additional sprouting. Within this network, 2 vessels already exist at the end of the 3rd week, which, not only connect with each other but even fuse. They are the 2 endocardial 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.

Note:

Chorionic villi: villi that develop from the 3rd week of pregnancy and form the placenta together with the decidua basalis.

Primitive streak: cell agglomeration in the dorsal caudal section of the embryonic disc with a primitive knot and primitive pit

Gastrulation: conversion of the bilaminar 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 develop.

Pathology of Pre-Embryology

Abortion

It has been verified that approximately 15% of all zygotes are aborted. One should assume, however, that the number of zygotes that are aborted in the first week of pregnancy is much greater than 15%, which might already be explained by the fact that the 1st week after fertilization is an extremely critical period in embryonic development. Successful embryonic development is related to a large number of conditions, such as the sufficient production of progesterone and estrogen, or chromosomal abnormalities of the zygote.

Rubella embryopathy

If a pregnant woman without rubella antibodies is infected with rubella during the first 3–4 months, the principally harmless rubella can lead to severe disturbances in the 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 Gregg’s syndrome, which consists of the triad: cataract, deafness, and a cardiac defect.

Alcohol embryopathy

Regular and 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 1 in every 200 newborns is affected.

Double formation

Double formation is an embryonic development disorder causing the initial embryonic entity to double. As a consequence, a partial separation of the 2 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

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 1% of Down syndrome patients, who do not only have cells with 47 chromosomes but also cells with 46 chromosomes.

Hydatidiform mole

Hydatid sagitt computed tomography image

Picture: ‘Hydatid sagittal computed tomography image’ by Hellerhoff. License: CC BY-SA 3.0

In the 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 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 3rd and 4th embryonic weeks caused by teratogenic medications, for instance. 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 exposed nervous tissue. If this happens in the head area, this is referred to as anencephaly.

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