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Chapter 2 - Gametogenesis

Fertilization is the process by which the male gamete (sperm) and female gamete (oocyte)
unite to give rise to a zygote.
Gametes are derived from primordial germ cells, formed in the epiblast during the second
week and that move to the wall of the yolk sac.
During the end of the fourth week they move towards the developing gonads, they arrive
by the end of the fifth week.
Germ cells undergo gametogenesis, in preparation for fertilization (includes meiosis and
cytodifferentiation).
Mitosis
Meiosis
Polar bodies: during meiosis, one primary oocyte gives rise to four daughter cells, each
with 22+1X chromosomes, but only one of these develops into a mature gamete, the
oocyte. The other three are polar bodies, receive little cytoplasm and degenerate during
subsequent development.
OOGENESIS
Oogenesis is the process whereby oogonia differentiate into mature oocytes.
Once PGCs have arrived in the gonad, they differentiate into oogonia. They undergo
several mitotic divisions, and by the end of the third month, they are arranged in clusters
surrounded by a layer of flat epithelial cells, called follicular cells.
Follicular cells originate form surface epithelium covering the ovary.
Most oogonia continue to divide by mitosis, but some of them arrest their cell division in
prophase of meiosis I and form primary oocytes.
Oogonia increase rapidly in number and by the fifth month the number of germ cells in the
ovary reaches its maximum, approx. 7 million.
Cell death begins, many oogonia and primary oocytes degenerate and become atretic.
By the seventh month the majority if oogonia have degenerated except for a few near the
surface.
All surviving primary oocytes have entered prophase of meiosis I, most of them are now
primordial follicles (primary oocytes surrounded by flat epithelial cells).
Primary oocytes remain arrested in prophase (diplotene stage, characterized by a lacy
network of chromatin) and do not finish their first meiotic division before puberty is
reached. This arrested state is produced by oocyte maturation inhibitor (OMI) a small
peptide secreted by follicular cells.
At puberty, a pool of growing follicles is established and continuously maintained from the
supply of primordial follicles. Each month 15-20 selected from this pool begin to mature.
When a follicle becomes atretic, the oocyte and surrounding follicular cells degenerate and
are replaced by connective tissue, forming a corpus atreticum.
Antral/vesicular stage: the surviving follicles from the selected ones accumulate fluid in
the antrum, such that immediately prior to ovulation, follicles are swollen and are called
mature vesicular follicles or Graffian follicles. (Antral stage - the longest mature
vesicular stage 37h prior to ovulation)
Primary follicles: as primordial follicles grow, surrounding follicular cells change from flat
to cuboidal and proliferate to form a stratified epithelium of granulosa cells, which rest on
a BM that separates them from surrounding ovarian CT, stromal cells, that form the theca
folliculi.
Zona pellucida: it is formed by granulosa cells and the oocyte, which secrete a layer of
glycoproteins on the surface of the oocyte.
Theca folliculi theca interna (inner layer of secretory cells) theca externa (outer
fibrous capsule). Small finger-like processes of the follicular cells extend across the zona
pellucida and interdigitate with microvilli of the plasma membrane of the oocyte, this is
important for transport of materials from follicular cells to the oocyte.
Vesicular follicle: fluid-filled spaces then appear between granulosa cells, these spaces
then grow together forming the antrum the follicle becomes a vesicular/antral follicle.
Granulosa cells surrounding the oocyte remain intact and form the cumulus oophorus.
Mature vesicular follicle (approx. 25 mm in diameter): surrounded by the theca interna
which has cells that secrete steroids, rich in blood vessels and the theca externa, which
gradually merges with the ovarian CT.
When the secondary follicle is mature, an increase in LH (luteinizing hormone) induces the
preovulatory growth phase meiosis I completed 2 daughter cells: secondary oocyte
(most of cytoplasm) and first polar body (almost no cytoplasm).
The first polar body lies between the zona pellucida and the cell membrane of the
secondary oocyte in the perivitelline space.
The cells enter meiosis II but arrests in metaphase 3h before ovulation, meiosis II is
completed only if the oocyte is fertilized, otherwise the cell degenerates approx. 24h after
ovulation.
The first polar body may undergo a second division.
SPERMATOGENESIS
Spermatogenesis begins at puberty, it includes the events by which spermatogonia are
transformed into spermatozoa.
Germ cells in the male infant can be recognized in the sex cords of the testis as large, pale
cells surrounded by supporting cells, which are derived from the surface epithelium like
follicular cells and later become sustentacular cells, or Sertoli cells.
Shortly before puberty sex cords acquire a lumen and become seminiferous tubules. At
about the same time, PGCs give rise to spermatogonial stem cells.
The production of type A spermatogonia, derived from this stem cell population, marks
the beginning of spermatogenesis.
Type A spermatogonia (dark and pale, clones formed from mitotic divisions) Type B
spermatogonia Primary spermatocytes Prophase of 22 days, completion of meiosis I
Secondary spermatocytes Meiosis II Spermatids.
Throughout these events cytokinesis is incomplete, so that successive cell generations are
joined by cytoplasmic bridges (the cell clones are kept in contact). They also remain
embedded in deep recesses of Sertoli cells, which support and protect the germ cells,
nurture them and assist the release of mature spermatozoa.
Spermatogenesis is regulated by LH production by the pituitary gland. LH binds on
receptors on Leydig cells that stimulates testosterone production, which binds to Sertoli
cells to promote spermatogenesis. FSH hormone binds to Sertoli cells and stimulates
testicular fluid production and synthesis of intracellular androgen receptor proteins.
Spermiogenesis: it is the series of changes resulting in the transformation of spermatids
into spermatozoa.
These changes include: 1) Formation of the acrosome (covers half of the nuclear surface
and contains enzymes to assist in penetration of the egg and surrounding layers during
fertilization); 2) Condensation of the nucleus; 3) Formation of neck, middle piece and tail;
4) Shedding of most of the cytoplasm (residual bodies phagocytized by Sertoli cells).
In humans, the development of a spermatogonium into a mature spermatozoon lasts
approx. 74 days, and approx. 300 million sperm cells are produced daily.
Spermatozoa then enter the lumen of seminiferous tubules, from where they are pushed
toward the epididymis by contractile elements in the wall of the seminiferous tubules.
In the epididymis spermatozoa obtain full motility.

Chapter 3 First Week of Development: Ovulation to Implantation


Ovarian cycles: sexual cycles are controlled by the hypothalamus. Gonadotropin releasing
hormone (GnRH) acts on cells of the adenohypophysis, which in turn secrete
gonadotropins. These hormones, FSH and LH, stimulate and control cyclic changes in the
ovary. FSH also stimulates maturation of follicular (granulosa) cells surrounding the oocyte.
In turn, proliferation of these cells is mediated by growth differentiation factor 9 (member
of the TGF beta family).
Theca interna and granulosa cells produce estrogens, and as a result: 1) The uterine
endometrium enters the follicular or proliferative phase; 2) The cervical mucus becomes
thinner to allow passage of sperm; 3) The anterior lobe of the pituitary gland is stimulated
to secrete LH.
At mid-cycle, there is an increase in LH that: 1) Elevates concentrations of maturation-
promoting factor, causing oocytes to complete meiosis I and initiate meiosis II; 2)
Stimulates production of progesterone by follicular stromal cells (luteinization); 3) Causes
follicular rupture and ovulation.
Ovulation: in the days preceding ovulation the vesicular follicle grows to a diameter of
25mm, under the influence if LH and FSH. It is now a mature vesicular follicle. This event
coincides with an abrupt increase in LH that causes the primary oocyte to complete meiosis
I the follicle enters the preovulatory mature vesicular stage. Meiosis II initiated but
arrested at approx. 3h before ovulation.
In the meantime, the surface if the ovary bulges locally and at the apex (avascular spot) the
stigma appears.
LH increase causes digestion of collagen fibers surrounding the follicle.
Prostaglandins level increases Local muscular contraction in the ovarian wall
extrusion of the oocyte, which breaks free with its surrounding granulosa cells from the
region of the cumulus oophorus (ovulation) and floats out of the ovary.
Corona radiata: some of the cumulus oophorus cells rearrange themselves around the
zona pellucida.
Corpus luteum: after ovulation, granulosa cells remaining in the wall of the ruptured
follicle, together with cells from the theca interna, are vascularized by surrounding vessels.
These cells then develop a yellowish pigment and change into lutein cells (under the
influence of LH). Lutein cells form the corpus luteum and secrete estrogens and
progesterone.
Progesterone (with some estrogen) causes the uterine mucosa to enter the progestational
or secretory stage, in preparation for implantation of the embryo.
Oocyte transport: shortly after ovulation, fimbriae sweep over the surface of the ovary,
and the tube begins to contract rhythmically. The oocyte, surrounded by some granulosa
cells is carried into the tube by these sweeping movements and my motion of cilia on the
epithelial lining.
Once the oocyte is in the uterine tube, it is propelled by peristaltic muscular contractions
of the tube and by cilia in the tubal mucosa. In humans this takes approx. 3 to 4 days.
Corpus Albicans: If fertilization does not occur, the corpus luteum reaches maximum
development approx. 9 days after ovulation corpus luteum shrinks because of
degeneration of lutean cells (luteolysis) and forms a mass of fibrotic scar tissue, the corpus
albicans. Simultaneously, progesterone production decreases, precipitating menstrual
bleeding.
If fertilization occurs, degeneration of the corpus luteum is prevented by human chorionic
gonadotropin, a hormone secreted by the syncytiotrophoblast of the developing embryo.
The corpus luteum grows and forms the corpus luteum of pregnancy: by the end of the 3rd
month it is one third to half the size of the ovary, Luteal cells continue to secrete
progesterone until the end of the 4th month. Then they regress slowly as secretion of
progesterone by the trophoblastic component of the placenta becomes adequate for
maintenance of pregnancy. (Removal of the corpus luteum of pregnancy before the 4 th
month usually leads to abortion)
Fertilization: it is the process by which male and female gametes fuse, it occurs in the
ampullary region of the uterine tube.
After reaching the isthmus, sperm become less motile and cease their migration. They
become motile again after ovulation (maybe because of chemoattractants produced by
cumulus cells surrounding the egg) and swim to the ampulla, where fertilization usually
occurs.
Spermatozoa cant fertilize the oocyte immediately upon arrival in the female genital tract
but must undergo:
1. Capacitation: it is a period of conditioning in the female reproductive tract that in
humans lasts approx. 7 hours. Most of the conditioning occurs in the uterine tube
and involves epithelial interactions between the sperm and the mucosal surface of
the tube. During this time, a glycoprotein coat and seminal plasma proteins are
removed from the plasma membrane that overlies the acrosomal region of the
spermatozoa. Only capacitated sperm can pass through the corona cells and
undergo the acrosome reaction.
2. Acrosome reaction: it occurs after binding to the zona pellucida and is induced by
zona proteins. It culminates in the release of enzymes needed to penetrate the
zona pellucida (acrosin- and trypsin-like substances).
Phases of fertilization:
Phase 1: Penetration of the corona radiata Only one spermatozoon fertilizes the egg, the
others are thought to aid it in penetrating the barriers protecting the female gamete.
Capacitated sperm pass freely through corona cells.
Phase 2: Penetration of the zona pellucida Release of acrosomal enzymes (acrosin)
allows sperm to penetrate the zona (a glycoprotein shell surrounding the egg that
facilitates and maintains sperm binding and induces the reaction), coming in contact with
the plasma membrane of the oocyte. Permeability of the zona pellucida changes when the
head of the sperm encounters the oocyte surface. This contact results in release of
lysosomal enzymes from cortical granules lining the plasma membrane of the oocyte, these
enzymes alter properties of the zona pellucida (zona reaction) to prevent sperm
penetration and inactivate species-specific receptor sites for spermatozoa on the zona
surface.
Phase 3: Fusion of the oocyte and sperm cell membranes After the adhesion of sperm to
oocyte the plasma membranes of the egg and posterior region of the sperm head fuse. In
humans, both the head and the tail of the spermatozoon enter the cytoplasm of the
oocyte, while the plasma membrane is left behind on the oocyte surface.
As soon as the spermatozoon has entered the oocyte, the egg responds in three ways:
1. Cortical and zona reactions. Because of the release of cortical oocyte granules,
which contain lysosomal enzymes, 1) the oocyte membrane becomes impenetrable
to other spermatozoa, and 2) the zona pellucida alters its structure and
composition to prevent sperm binding and penetration. Prevent polyspermy
(penetration of more than one spermatozoon into the oocyte).
2. Resumption of the second meiotic division. The oocyte finishes meiosis II as the
spermatozoon enters. One of the daughter cells, which receives hardly any
cytoplasm, is known as the second polar body; the other cell is the definitive
oocyte. Its chromosomes arrange themselves in a vesicular nucleus, the female
pronucleus.
3. Metabolic activation of the egg. Cellular and molecular events associated with
early embryogenesis.
Meanwhile, the spermatozoon moves forward until it lies close to the female pronucleus.
Its nucleus becomes swollen and forms the male pronucleus, the tail detaches and
degenerates. The two nuclei eventually come in contact and lose their nuclear envelopes.
During their individual growth, each duplicates its DNA. After DNA synthesis, chromosomes
organize on the spindle in preparation for a normal mitotic division.
The main results of fertilization are:
1. Restoration of the diploid number of chromosomes, half from the father and half
from the mother.
2. Determination of the sex of the new individual.
3. Initiation of cleavage.
Cleavage: once the zygote has reached the two-cell stage, it undergoes a series of mitotic
divisions, increasing the number of cells. These cells are known as blastomeres. They form
a loosely-arranged clump until the 8-cell stage, the morula.
Then compaction occurs: it is a process in which inner cells are segregated from the outer
cells (inner cells are in a compact ball held together by tight junctions, and communicate by
gap junctions).
The inner cell mass gives rise to tissues of the embryo proper, and the outer cell mass
form the trophoblast, which later contributes to the placenta.
Blastocyst formation: when the morula enters the uterine cavity, fluid begins to penetrate
through the zona pellucida into the intercellular space of the inner cell mass.
Gradually the intercellular spaces become a single cavity, the blastocele. the embryo is
a blastocyst.
Cells of the ICM, now called the embryoblast, are at one pole, and those of the OCM, or
trophoblast, flatten to form the epithelial wall of the blastocyst. The zona pellucida has
disappeared, allowing the beginning of implantation.
Initial attachment of the blastocyst to the uterus is thought to happen on about the 6th
day, and it is mediated by L secretin on trophoblast cells and its carbohydrate receptors.
Selectins and integrins are the proteins involved in the process, which also includes signal
transduction pathways to regulate trophoblast differentiation, thus implantation is the
result of mutual trophoblastic and endometrial action.
Uterus at the time of implantation: the wall of the uterus consists of three layers:
1. Endometrium or mucosa lining the inside wall
2. Myometrium, a thick layer of smooth muscle
3. Perimetrium, the peritoneal covering lining the outside wall
During the menstrual cycle, the uterine endometrium passes through three stages, the
1. Follicular or proliferative phase. It begins at the end of the menstrual phase, it is
under the influence of estrogen. It is parallel to the growth of the ovarian follicles.
2. Secretory or progestational phase. It begins approx. 2-3 days after ovulation in
response to progesterone produced by the corpus luteum. If fertilization doesnt
occur, shedding of the endometrium marks the beginning of the menstrual phase. If
fertilization occurs, the endometrium assists in implantation and formation of the
placenta.
3. Menstrual phase.
At the time of implantation, the mucosa of the uterus is in the secretory phase, during
which the uterine glands and arteries become coiled and the tissue fleshy 3 different
layers can be recognized:
1. A superficial compact layer;
2. An intermediate spongy layer;
3. A thin basal layer
Normally, the blastocyst implants in the endometrium along the anterior or posterior wall
of the body of the uterus, where it becomes embedded between the opening of the
glands.
If fertilization doesnt occur, venules and sinusoidal spaces gradually become packed with
blood cells, when the menstrual phase begins, blood escapes from superficial arteries and
small pieces of stroma and glands break away. In the following 3-4 days the compact and
spongy layers are expelled from the uterus, and the basal layer is retained.
The basal layer is supplied by its own arteries, the basal arteries, and works as the
regenerative layer in the rebuilding of glands and arteries in the prolipherative phase.

Chapter 4 Week of 2s
This chapter is a description of the second week of development. It should be kept in mind
that even at this early stage the growth rate has significant variances between individuals.
o Day 8
At the wake of this day, the blastocyst is partially embedded in the endometrial stroma.
Trophoblasts in the area over embryoblasts differentiate in two layers:
Mononucleated cells called cytotrophoblasts - Inner layer
Multinucleated zone called syncytiotrophoblasts Outer layer
Mitosis is found in the inner and not in the outer layer, thus cytotrophoblasts divide and
migrate into the syncytiotrophoblasts, where they fuse and lose their individual
membrane.
Embryoblasts of the inner cell mass differentiate in two layers as well:
Small cuboidal cells adjacent to the blastocyst cavity, called hypoblast layer
High columnar cells adjacent to the amniotic cavity, the epiblast layer
All layers form a flat disc, and at the same time, a small cavity appears within the epiblast
layer, and precisely within those called amnioblasts, enlarging to become the amniotic
cavity. The glands present in the endometrial stroma, highly vascularised and oedematous,
secrete glycogen and mucus.
o Day 9
The blastocyst is more deeply embedded into the endometrium and penetration defects
are closed by a fibrin coagulum. Following the deeper embedding into the endometrium,
syncytiotrophoblasts at the embryonic pole develop considerably, forming vacuoles that
fuse to form interconnected lacunae: this is referred to as the lacunar stage of trophoblast
development. At the abembryonic pole, hypoblasts give rise to the exocoelomic (Heusers)
membrane, lining the exocoelomic cavity, or primitive yolk sac, formed at the centre of
cytotrophoblasts.
o Days 11 and 12
Blastocyst embedding in the endometrial stroma is completed, and surface epithelium has
almost completely covered the original defect. Concurrently, syncytiotrophoblasts erode
the endothelium of more and more maternal capillaries, known as sinusoids. Syncytial
lacunae become continuous with these vessels, and maternal blood enters the lacunar
system, eventually establishing the uteroplacental circulation.
As this process progresses, the extraembryonic mesoderm, derived from yolk sac cells,
appears between the inner surface of the cytotrophoblasts and the outer surface of the
exocoelomic cavity. These newly formed cells eventually fill all the space between the
trophoblasts, left externally, and the amnion and exocoelomic cavity, left internally. Large
cavities develop in the extraembryonic mesoderm and eventually become continuous,
creating the extraembryonic or chorionic cavity. This space surrounds the primitive yolk
sac and amniotic cavity, except where the germ disc is connected to the trophoblast by the
connecting stalk. The extraembryonic mesoderm divides in two layers:
The extraembryonic somatic mesoderm lines the cytotrophoblasts and amnion
The extraembryonic splanchnic mesoderm covers the yolk sac
In the meantime, growth of the bilaminar disc remains very small (0.1-0.2 mm), while the
cells of the endometrium undergo the decidua reaction: they load with glycogen and
lipids, intercellular spaces are filled with extravasate, and the tissue is oedematous.
o Day 13
The surface defect in the endometrium is usually completely healed at this point.
Occasionally, however, bleeding occurs at the implantation site from the lacunar spaces.
This bleeding is sometimes mistaken with normal menstrual bleeding.
Cytotrophoblasts protrude into the syncytiotrophoblasts forming primary villi.
Hypoblasts proliferate along the inside of the exocoelomic membrane, forming, within the
exocoelomic cavity, a new and much smaller cavity known as secondary or definitive yolk
sac. During its formation, large portions of the exocoelomic cavity are pinched off, forming
the exocoelomic cysts, which are often found in the extraembryonic coelom. This cavity
expands, taking the name of chorionic cavity, whose cytotrophoblast lining is named
chorionic plate. The only area where the extraembryonic mesoderm traverses the
chorionic cavity is the connecting stalk, which will become the umbilical cord.
Clinical correlation: implantation may also occur outside the uterus, such as in Douglas
pouch, one the mesentery, in the uterine tube, or in the ovary.

Chapter 5 Trilaminar Germ Disc


Gastrulation: formation of embryonic mesoderm and endoderm
Gastrulation is the main event of the third week: it establishes all three germ layers in the
embryo.
Formation of the primitive streak on surface of the epiblast. Its cephalic end is named
primitive (Hensens) node, forming a slightly bulging region surrounding the primitive pit.
Streak cells secrete fibroblast growth factor 8, a transcriptional inhibitor of E-cadherin, the
protein binding epiblasts together, thus promoting the process of invagination: epiblast
cells migrate toward the primitive streak, and when they reach it, they become flask-
shaped, detach from the epiblast and slip beneath it.
The invaginated cells, still under the effects of FGF8, specify: some displace the hypoblasts,
creating the embryonic endoderm, while others come to lie between the epiblast and the
newly created endoderm forming the embryonic mesoderm. Cells of the epiblast are now
regarded as embryonic ectoderm
Cells moving between the epiblast and hypoblast layers eventually begin to spread laterally
and cranially.
o Beyond the margin of the disc establish contact with the extraembryonic
mesoderm covering the yolk sac and amnion
o In the cephalic direction, they pass on each side the prechordal plate, a structure
which will be important in induction of the forebrain, and which forms between the
tip of the notochord and the oropharyngeal membrane. This last structure at the
cranial end of the disc consists of a small region of tightly adherent ectoderm and
endoderm cell that represents the future opening of the oral cavity.
Formation of the notochord
Prenotochordal cells invaginating in the primitive node move cranially in the midline until
they reach the prechordal plate. These cells become so intercalated in the hypoblast layer
that, momentarily, the midline of the embryo consists of two cell layers that form the
notochordal plate. When hypoblasts are replaced by endoderm cells invaginating at the
streak, notochordal cells proliferate and detach from the endoderm, forming a solid cord
of cells, the definitive notochord, which underlies the neural tube and will provide the
axial skeleton. The cranial end is formed first, reaching the prechordal plate, and later the
caudal, reaching the primitive pit. Where the pit forms an indentation in the epiblast layer,
the neurenteric canal temporarily connects amniotic and yolk sac.
The cloacal membrane is formed at the caudal end of the embryonic disc by two closely
adherent layers of ectoderm and endoderm without any intervening mesoderm. When this
membrane appears, the yolk sac forms the allantois, a small diverticulum, into the
connecting stalk. Its function is probably vestigial in humans, but it may be involved in
abnormalities of bladder development.
Establishment of body axes
Body axes (anteroposterior, dorsoventral, left-right) takes place before and during
gastrulation.
Anteroposterior axis
o It is established at the cranial margin of the embryonic disc. This area, the anterior
visceral mesoderm (AVE), expresses genes essential for head formation (e.g. OTX2,
LIM2, HESX1), and secreted factors cerberus and lefty, which inhibit nodal activity
in the cranial end of the embryo before gastrulation.
o The primitive streak is maintained and initiated by expression of Nodal, a b
transforming growth factor. Once the streak is formed, Nodal upregulates a
number of genes responsible for formation of dorsal and ventral mesoderm and
head and tail structures.
Dorsoventral axis
o Another TGF-b, bone morphogenic protein 4 (BMP4), if present with FGF,
ventralizes mesoderm to contribute to kidneys (intermediate), blood and body wall
(lateral mesoderm).
o All mesoderm would be ventralized, were not it for the node, denominated the
organizer: chordin, noggin and follistatin antagonize the activity of BMP4, resulting
in cranial mesoderm being dorsalized into notochord, somites and somatomeres.
o The same role Nodal has in initiating and maintaining the primitive streak is covered
by HNF-3 for the node and later induces regional specificity in the forebrain and
midbrain areas.
o Goosecoid is the transcription factor for HNF-3, noggin, chordin and follistatin.
Failing in regulation of these factors will result in sever malformations of the head
(e.g. duplication).
o The Brachiury gene regulates dorsal mesoderm formation in middle and caudal
regions of the embryo. This gene is essential for cell migration through the primitive
streak, due to the fact that it codes for a very prolific transcription factor, and its
absence results in shortening of the embryonic axis.
Laterality is orchestrated by a cascade of signal molecules and genes.
o When the primitive streak appears, FGF8 is secreted by cells in the node and
primitive streak and induces expression of Nodal, but only on the left side
o As the neural plate is established, FGF8 maintains Nodal and LEFTY-2 expression on
the left side of the embryo: both of these upregulate PITX-2. PITX-2 is transcription
factor responsible for establishing left-sidedness in the whole body and organs, as
they assume their asymmetrical position inside the body. Expression defects result
in dextrocardia and situs inversus.
o At the same time, LEFTY is expressed on the left side of the floor plate of the neural
tube and may act as a barrier to prevent left-sided signals from crossing over. Sonic
hedgehog may also help in this function.
o Serotonin also has a fundamental role: it concentrated mainly on the left side, and
is upstream from FGF8 signaling. Alterations in serotonin signalling result in situs
inversus, dextrocardia and a variety of heart defects.
o Transcription factors for the right side have not yet been fully identified, but Snail
factor is restricted to the right lateral plate mesoderm and probably regulates
effector genes responsible for establishing the right side.
Fate map established during gastrulation
Depending on the position of ingress of a cell into the primitive streak, it will end in a
different position:
o Cranial region of the node prechordal plate and notochord
o Lateral edges of the node and from cranial end of the streak paraxial mesoderm
o Midstreak region intermediate mesoderm
o Caudal part of the streak lateral plate mesoderm
o Caudalmost part of the streak contribution to extraembryonic mesoderm
(together with primitive yolk sac)
Growth of the embryonic disc
The embryonic disc gradually becomes elongated, broadening cranially and narrowing
caudally due to cell migration from the primitive streak forward and laterally. The caudal
primitive streak continues to provide new cells, resulting in continuation of gastrulation in
the caudal end while differentiation is already happening in the cranial region: the embryo
develops cephalocaudally.
Further development of the trophoblast
By the beginning of the third week, the trophoblast is characterized by primary villi,
consisting of a cytotrophoblastic core covered by a syncytial layer. Mesoderm protrudes in
these villi, constituting secondary villi. Core cells of these secondary villi begin to
differentiate into blood cells and small blood vessels forming the villous capillary system.
The villus is now known as a tertiary/definitive placental villus. Capillaries in these latter
villi make contact with capillaries developing in the mesoderm of the chorionic plate and in
the connecting stalk. These vessels connect the placenta and the embryo: when the heart
begins to beat in the fourth week, the villous system is ready to supply essential nutrients
and oxygen.
In the meantime, cytotrophoblastic cells in villi penetrate progressively into the overlying
syncytium until they reach maternal endometrium. Here, they establish contact with
similar extensions of neighbouring villous stems, forming a thin outer cytotrophoblast
shell. This shell surrounds the trophoblast entirely and attaches the chorionic sac firmly to
the maternal endometrium. These villi are called stem or anchoring villi, and they extend
from the chorionic plate to the decidua basalis. Those branching from the sides of the
stem villi are free villi, through which exchange of nutrients will occur. The chorionic cavity
becomes larger and by day 20 the embryo is attached to its trophoblastic shell by a narrow
connecting stalk, which will later develop into the umbilical cord.