THE FIRST WEEK OF DEVELOPMENT

Is the period from FERTILIZATION to IMPLANTATION

FERTILIZATION
The fertilization represents the totality of phenomenons from the contact between the haploid
female gamete and the haploid male gamete (the fusion of their genetic material) to the first
metaphase of the mitotic division of the diploid zygote.
The end of fertilization become thus the first phase of ontogenesis, the start of the
development of the embryo.
From the millions of sperm which are deposited into vagina, only a few thousands cross the
uterine cavity and only a few hundreds arrive in the ampullary region of the uterine tube, the place
where the fertilization occurs. This ampullary region of the uterine tube is the widest part of the tube
and is close to the ovary.
The fertilization is formed by two phenomenon: a) the fusion of the spermatozoon with the
second oocyte; 2) the activation of the oocyte.
Spermatozoa are not able to fertilize the oocyte immediately upon arrival in the female
genital tract, they must undergo (1) capacitation and (2) the acrosome reaction to acquire this
capability.
1. Capacitation
- is a period of conditioning in the female reproductive tract that lasts approximately 7 hours.
- during this time, a glycoprotein coat and seminal plasma proteins are removed from the
plasma membrane that overlies the acrosomal region of the spermatozoa.
- the capacitation occurs in the uterine tube or uterus and involves epithelial interactions
between the sperm and the secretions from the feminine genital tract and follicular liquid.
2. The acrosome reaction:
- occurs in the same time when the spermatozoon pass through the corona radiata.
- only the capacitated spermatozoa undergo acrosomal reaction
- during this phase the acrosomal membrane fuse in several places with the membrane of the head of
the spermatozoon; in that places of fusion, the membranes break, they are perforated. This reaction
culminates in the release of enzymes needed to penetrate the corona radiata, including acrosin, zona
lysine, hyaluronidase.
The fertilization lasts almost 24 hours and is formed by several phases:
1. The dispersion of the follicular cells and the penetration of corona radiata, which are realized
by the action of hyaluronidase and the movements of the sperm.

2. The penetration of the zona pellucida: which is realized by the actions of acrosin and zona
lysine. Release of acrosomal enzymes allows sperm to penetrate the zona, thereby coming in
contact with the plasma membrane of the oocyte.
- Permeability of the zona pellucida changes when the head of the sperm comes in contact
with the oocyte surface. This contact results in release of lysosomal enzymes from
cortical granules lining the plasma membrane of the oocyte. In turn, these enzymes alter
properties of the zona pellucida (zona reaction) to prevent sperm penetration on the zona

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 surface. These reactions prevent polyspermy (penetration of more than one
spermatozoon into the oocyte).

3. Fusion of the oocyte and sperm cell membranes: in this phase the membrane that covers the
sperm head fuse with the oocyte membrane, and thus the head and the tail of the
spermatozoon enter the cytoplasm of the oocyte.

4. The oocyte reaction: As soon as the spermatozoon has entered the oocyte, the egg responds in
two ways:
- the contraction of the oocyte’s cytoplasm forming the perivitelline space which contains
liquid and cortical granules, that are obstacles for the penetration of others spermatozoa.
- The oocyte finishes its second meiotic division immediately after entry of the spermatozoon.
One of the daughter cells, which receives hardly any cytoplasm, is known as the second polar
body; the other daughter cell is the definitive oocyte (haploid). Its chromosomes (22 plus X)
arrange themselves in a vesicular nucleus known as the female pronucleus.

5. The formation of the pronuclei and their fusion:

After the sperm enters the cytoplasm of the oocyte, the tail degenerates, but the head (which
contains the nucleus) become the male pronucleus.
The nucleus of the definitive oocyte become female pronucleus. During growth of male and
female pronuclei (both haploid), each pronucleus must replícate its DNA. If it does not, each cell of
the two-cell zygote has only half of the normal amount of DNA.
The fusion of the two pronuclei occurs after doubling their DNA quantity. The result of this phase
is the zygote. Thus, the zygote is diploid unicellular cell that has 46 chromosomes.
After the fusion of the two pronuclei, immediately the maternal chromosomes mix up with
the paternal chormosomes. At the same time, immediately after DNA synthesis, chromosomes
organize on the division spindle in preparation for a normal mitotic division. The 23 maternal and 23
paternal (double) chromosomes split longitudinally at the centromere, and sister chromatids move to
opposite poles, providing each cell of the zygote with the normal diploid number of chromosomes and
DNA. As sister chromatids move to opposite poles, a deep furrow (groove) appears on the surface of
the cell, gradually dividing the cytoplasm into two parts. This moment, when the chromosomes
arrange into a double equatorial plaque, represent the end of fertilization and the begining of the
cleavage.

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 The consequences of fertilization are:
- The activation of the secondary oocyte, which finishes its secondary meiotic division;
- Initiation of cleavage. Without fertilization, the oocyte usually degenerates 24 hours after
ovulation.
- Restoratíon of the diploid number of chromosomes (46), half from the father and half
from the mother. Hence, the zygote contains a new combination of chromosomes
different from both parents; in this way, the fertilization provide the transmission of
hereditary features.
- Determination of the sex of the new individual. An X-carrying sperm produces a female
(XX) embryo, and a Y-carrying sperm produces a male (XY) embryo. Therefore, the
chromosomal sex of the embryo is determined at fertilization.
- The fertilization introduces the centrioles which are lacking in the mature egg. The
centrioles are two very small particles inside the cytoplasm of the cell, near the nucleus,
during the division time. The spindle forms between the two centrioles.

THE CLEAVAGE

The cleavage occurs immediately after fertilization.

Once the zygote has reached the two-cell stage, it undergoes a series of mitotic divisions,
increasing the numbers of cells. These cells, which become smaller with each cleavage division,
are known as blastomeres.
The zygote is a large cell, with predomination of the cytoplasmic mass; between two
successive divisions, the quantity of nuclear mass increase, but the quantity of cytoplasmic mass
remains constant. Thus, at the end of the cleavage, the blastocyst that results isn’t bigger than the
initial zygote.

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 The cleavage occurs during the movement of the zygote from the fallopian tube to the uterine cavity.
Approximately 3 days after fertilization, cells of the compacted embryo divide again to
form a 16-cell morula (mulberry). Inner cells of the morula constitute the inner cell mass, and
surrounding cells compose the outer cell mass. The inner cell mass gives rise to tissues of the
embryo proper, and the outer cell mass forms the trophoblast, which later contributes to the
placenta.
The formation of the blastocyst
As a result of the cleavage, at 30 hours after the fertilization were formed 2 blastomeres, at
50 hours – 4 blastomeres, at 72 hours – 12-16 blastomeres which formed a group called morula. In
this morula stage, the zygote enters into the uterine cavity where it remains free another 2-3 days,
during which the cleavage continues.
In the fourth day of intrauterine life, inside the morula penetrates fluid from the uterine
cavity into the intercellular spaces. Gradually, the intercellular spaces become confluent, and finally,
form a single cavity, the blastocele. At this time, the embryo is a blastocyst. Cells of the inner cell
mass, now called the embryoblast, are at one pole, and those of the outer cell mass, or trophoblast,
flatten and form the epithelial wall of the blastocyst.
In the fifth day, the zona pellucida disappears allowing the implantation to begin, and at the
end of this day or at the beginning of the sixth day, this group of cells (blastocyst) attaches to the
endometrium. Trophoblastic cells over the embryoblast pole begin to penetrate between the epithelial
cells of the uterine mucosa (endometrium). The endometrium assists in implantation and contributes
to formation of the placenta. This moment marks the end of the free period of the embryo and the
beginning of the gestation.

Hence, by the end of the first week of development, the human zygote has passed through
the morula and blastocyst stages and has begun implantation in the uterine mucosa, along the anterior
or posterior wall.
The implantation of the embryo
In the sixth-seventh day after the fertilization, the blastocyst is implanted into the uterine
mucosa. The adhesion of the embryo to the uterine epithelium is realised at the pole that contains the
embryoblast (group of young cells that develop the embryo), normally into the posterior wall of the
uterus, in its superior 1/3.
In this place, the trophoblast (the peripheral cells that surround the blastocyst) grow and
differentiates into two layers: (1) an inner layer of mononucleated cells, the cytotrophoblast, and
(2) an outer multinucleated zone, the syncytiotrophoblast (to the uterine mucosa).
The syncytiotrophoblast, through digitiform extensions and through enzymes activity
penetrates the uterine mucosa which presents signs of degeneration; when the penetration process

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contact the sanguine vessels of the endometrium it appears a small haemorrhage (implantation
haemorrhage).
After it is stabilize an enzymatic equilibrium between the uterine mucosa and the egg, the
blastocyst become more deeply embedded in the endometrium, and the penetration defect in the
surface epithelium is closed by a fibrin coagulum.
Until the implantation, the embryo is feed by its own reserves and by the liquid inside the
female genital tract; this is named embryotrophic period.
After the embryo is implanted, it is feed by the cellular parts of the uterine mucosa that is
digested by syncytiotrophoblast – the histiotrophic period.
Under the influence of progesterone, some transformations occurs in the uterine mucosa to prepare it
for the implantation of the egg:
- Hypertrophy of the uterine mucosa through edema ;
- The large, tortuous uterine glands secrete abundant glycogen and mucus.
- Vascular hyperemia.

In the seventh day, the first embryonic layer begins to appear, the hypoblast layer (primary
endoderm). The genetic marker of this first week period is a gestational protein named alpha-
fetoprotein.

THE SECOND WEEK OF DEVELOPMENT

This period is characterized by two processes:
1. The end of implantation
2. The transformation of the embryoblast into a bilaminar germ disc

1. The end of implantation

In the ninth day, the blastocyst is deeply embedded into the epithelial stroma, completely
implanted and the penetration defect in the surface epithelium is closed by a fibrin coagulum which
determine a slight protrusion on the endometrial surface.
The endometrial cells, sanguine vessels, uterine glands and syncytiotrophoblast undergo
some changes necessary for the feeding of the blastocyst; all of those changes represents the decidual
reaction.

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 In the tenth and eleventh days, the trophoblast shows considerable progress in
development, particularly at the embryonic pole, where vacuoles appear in the syncytium. Those
lacunar spaces in the syncytiotrophoblast form an intercommunicating network that is particularly
evident at the embryonic pole and it represents the primordium of the intervillous spaces.
In the 12th day, the cells of the syncytiotrophoblast penetrate deeper into the stroma and
erode the maternal capillaries. These capillaries, which are congested and dilated, are known as
sinusoids. The syncytial lacunae become continuous with the sinusoids, and maternal blood enters the
lacunar system. As the trophoblast continues to erode more and more sinusoids, maternal blood
begins to flow through the trophoblastic system, establishing the uteroplacental circulation.
In the 12-13th day the original defect in the uterine wall is completely repaired by the
proliferation of the endometrial epithelium, the blastocyst is completely embedded in the uterine
mucosa.
In the 13th day the decidual reaction is spread on a large area and the primary villi appear.
In this day the trophoblast is characterized by villous structures. Cells of the cytotrophoblast
proliferate locally and penetrate into the syncytiotrophoblast, forming cellular columns surrounded by
syncytium. Cellular columns with the syncytial covering are known as primary villi.

2. The stages of the bilaminar germ disc formation

In the 8th day, between the embryoblast and cytotrophoblast are formed spaces which
confluence into a small cavity – the amniotic cavity.
The embryoblast become a flattened disc with two layers:
- The first layer consists of high columnar cells that line the amniotic cavity and form the
epiblast layer, from which almost all the embrionic cells will be derived.
- The second layer consists of small cuboidal cells adjacent to the blastocyst cavity, known
as the hypoblast layer (primitive embryonic endoderm). Those cells are pushed out to
the outside of the embryonic disc and form a thin membrane: the exocoelomic (Heuser)
membrane that lines the inner surface of the cytotrophoblast.
The amniotic cavity raise, the cytotrophoblast divides and a new layer of cells appear to
line the amniotic cavity; they are the amnioblasts (which form the amnion membrane of the
cytotrophoblast) surrounded at the periphery by the epiblast.
In the 9th day, from the hypoblast is formed the exocoelomic membrane.This membrane,
together with the hypoblast, forms the lining of the exocoelomic cavity, or primitive yolk sac.
In 11-12th days a new population of cells appears between the inner surface of the
cytotrophoblast and the outer surface of the exocoelomic cavity. These cells form a fine connective
tissue, a network, the extraembryonic mesoderm, which surrounds the amnion and primitive yolk
sac.
In the 12th day large cavities develop in the extraembryonic mesoderm, and when these
become confluent, they form a new space known as the extraembryonic cavity, or chorionic cavity.
This cavity divides the mesoderm into two layers. The extraembryonic mesoderm lining the
cytotrophoblast and amnion is called the extraembryonic somatic mesoderm; the lining covering
the yolk sac is known as the extraembryonic splanchnic mesoderm.
Extraembryonic somatic mesoderm together with cytotrophoblast form the chorion (it is
like a sac which contains the embryo and its amnion).

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 In the 13th day, the median part of the hypoblast layer become high and adherent to the
epiblast layer, forming the prechordal plate. This prechordal plate is an organizer for the head
region, from which will develop the mesoderm of the head and the endodermal layer of the
oropharyngeal membrane. This oropharyngeal membrane develops at the cranial end of the disc
and consists of a small region of tightly adherent ectoderm and endoderm cells that
represents the future opening of the oral cavity.

At the end of the second week, the embryo is a bilaminar germ disc situated between two
cavities filled with liquid (the amniotic cavity and the yolk sac). Both cavities are suspended into a
large cavity (the extraembryonic coelom or chorionic cavity) and all those structures together measure
approximately 2 mm. The cephalic region of the embryo begins to form through the prechordal plate.

The second week of development is known as the week of 2’s:

1. The trophoblast differentiates into 2 layers: the cytotrophoblast and syncytiotrophoblast
2. The embryoblast forms 2 layers: the epiblast and hypoblast
3. The extraembryonic mesoderm splits into 2 layers: the somatic and splanchnic layers
4. Two cavities form: the amniotic and yolk sac cavities