INTRODUCTION TO HUMAN EMBRYOLOGY
A.HENRY SATHANANTHAN
Monash Institute of Reproduction & Development, Monash
University, Melbourne
henry.sathananthan@med.monash.edu.au
OBJECTIVES OF THIS CHAPTER
To introduce you to:-
1.
The first 8 weeks of human development – the embryonic period.
2.
The processes of fertilization, cleavage, germ layer formation and primary
organogenesis.
3.
Some clinical aspects of these processes.
4.
Physiology of the embryo – placentation.
5. Critical
periods of development and some congenital malformations.
6. Basic
texts, atlases, slides and CD-ROMs, since embryology is a visual subject.
INTRODUCTION
Embryology deals with the
study of the human embryo during the first 8 weeks of development. It is
important to know the events that occur in the beginnings of life, when all the
blueprints of the human body are laid down in the embryo. The embryonic period
is followed by the foetal period (months 3-9) when there is extensive growth
and differentiation and when the embryo acquires a more human form (see
separate chapter). Development is a long complex process which transforms a
single cell (fertilized ovum) into a complex multicellular organism. The development
of the embryo and foetus is the prenatal period of development.
[A timetable of prenatal
development is illustrated in Moore, 1989]
Development is a
complex process which transforms a single cell into a complex multicellular
organism.
EMBRYONIC
PERIOD
Embryonic development begins at fertilization (day
1) followed by cleavage of the embryo and its
implantation in the uterus (week 1). This is
followed by the differentiation of the primary germ layers (week 3) and
culminates in primary organogenesis when the tissues and major organ rudiments
of the embryonic body are formed (weeks 4-8). The embryonic period may be
temporally considered in 4 phases:-
First Week: Fertilization, cleavage and onset of implantation
(pre-implantation phase).
Second Week: Formation of bilaminar embryo, deep
implantation and establishment of uteroplacental circulation.
Third Week: Formation of trilaminar
embryo (gastrulation), somites, chorionic villi and neurulation.
Fourth to Eighth Weeks: Formation of the embryonic
body, primary organogenesis and placentation.
The physiology of the embryo
(foetal membranes and placenta) and some congenital malformations during
critical periods of development will also be dealt with in this chapter.
THE FIRST
WEEK: Gametes, Fertilization, Cleavage and Implantation
The pre-implantation phase
of development begins with fertilization and culminates in the implantation of
the blastocyst in the uterine endometrium. Our knowledge of the first week of
development has advanced immensely in the past 20 years, since the advent of in
vitro fertilization (IVF) and assisted reproductive technologies (ART). [See our atlas of Early Human Development
for ART – Sathananthan et al 1993;1996 for illustrations.]
a) Gamete structure: sperm and egg
Briefly, the spermatozoon is a highly specialized
torpedo-shaped cell (~ 30mm long) for motility and,
of course, for fertilization. It is
composed of a head, midpiece (body) and a tail (flagellum). The head carries
the nucleus with the paternal chromosomes and is capped by a modified lysosome
(acrosome) covered by the cell membrane. The midpiece consists of the base of
the axoneme originating from the sperm-neck, where is located the functional
paternal centriole hidden in a “black box”. The midpiece has a spiral of
mitochondria around the axoneme which provides ATP for sperm motility and nine
dense fibres surrounding the axoneme. The axoneme consists of 9 peripheral
doublets and a central doublet of microtubules (9+2 organization) that extends
into the tail, characteristic of cilia and flagella and is the motile component
of the cell. The tail has a ring of 7 dense fibres and a fibrous sheath around
the axoneme.
The spermatozoon is a highly specialized cell for motility and
fertilization.
The mature egg or oocyte is a large unspecialized
cell (~120mm in diameter) compared to the spermatozoon.
It has no nucleus but has a maturation spindle arrested at metaphase II of
meiosis. The spindle is barrel-shaped and aligned at right angles to the oocyte
surface, where the first polar body is located within the PVS. The egg
vestments consist of a gelatinous zona pellucida (shell) surrounded by several
layers of follicle cells that make up the cumulus oophorus. The cumulus is
expanded and gelatinous in mature oocytes. The egg cell has most of the
components of somatic cells but lacks rough endoplasmic reticulism. It has
cortical granules beneath the cell membrane, which play a role in
fertilization.
[See our
atlases Sathananthan et al, 1993; 1996 published by the department for details
of gamete structure and function, and CD-ROM, Sathananthan & Edwards, 1995]
The oocyte is a large unspecialized cell compared to the
spermatozoon
b)
Gamete transport
Mature sperm (several millions) are ejaculated into
the vagina after intercourse, enter the uterus through the cervix and swim up
to the far end of the oviduct (ampulla) in about 5 minutes, where fertilization
occurs. Of the millions ejaculated, only a few hundred reach the ampulla. These
are the most motile in the ejaculate. Sperm capacitation (a physiological
process) occurs somewhere in the reproductive tract, where sperm acquire the
ability to penetrate the vestments of the oocyte. In vitro, it takes place
during the sperm preparation procedure (washing and layering) for ART. Once at
the surface of the egg, it has to penetrate the cumulus oophorus (follicle
cells around the egg) and the gelatinous shell (zona pellucida) before gamete
fusion occurs. Penetration is aided by sperm motility and the acrosome reaction
(AR), which is the morphological expression of capacitation. During the AR the
surface membranes of the acrosome
vesiculate releasing 2 important enzymes – hyaluronidase and acrosin (protease), which enable sperm to penetrate
the cumulus and zona, respectively, and reach the perivitelline space (PVS)
surrounding the egg.
Sperm penetration is aided by sperm motility and the acrosome
reaction
The mature egg (oocyte) is ovulated around day 14 of
the natural menstrual cycle [See Moore, (1989);
Larsen, (1998)], released from the ovary into the peritoneal cavity and
immediately sucked up through the infundibulum of the Fallopian tube (oviduct)
by its ciliary action into the ampulla. Here fertilization occurs and
development begins. Oocytes remain
viable for up to 12 hours after ovulation, while sperm can survive up to 24
hours in vivo. Sperm, however can be kept alive in vitro up to 2-3 days and
still retain their fertilizing capacity, while eggs too can survive for about
20-24 hours, in vitro.
Fertilization occurs in the ampulla of the oviduct soon after
ovulation
c) Fertilization
This involves the spontaneous fusion of two germ
cells – sperm and egg – to form a zygote. The zygote or fertilized egg is the first
cell of the new baby. Fertilization essentially restores the diploid number (2n
= 46) of chromosomes of somatic (body) cells bringing the father’s and mother’s
genomes together.
The mature sperm cell is formed in the testis (male
gonad) by a process of meiotic maturation called spermatogenesis, while the
mature oocyte is formed likewise in the ovary (female gonad) during oogenesis.
Each gamete has a haploid number of chromosomes (n = 23), having undergone
meiosis (reduction division) during gametogenesis (formation of gametes). The
zygote has the diploid number of chromosomes (2n = 46). Biparental inheritance
of chromosomes leads to species variation, since there is independent
assortment of paternal and maternal chromosomes among the germ cells during
meiosis. Sex is also determined at fertilization.
Fertilization involves the spontaneous fusion of
two germ cells – sperm and egg – to form a zygote
d) Mechanics of fertilization
The major events that take place simultaneously or
soon after fertilization are summarized as follows:
(i)
Sperm
– oocyte fusion: the midsegment of the sperm membrane fuses with that of the
egg followed by sperm incorporation into the egg to form a male pronucleus
(MPN).
(ii)
Soon
after gamete fusion there is a sperm-induced calcium wave in human oocytes.
(iii)
The
egg completes its second maturation division, abstricting the second polar body
and a female pronucleus (FPN) is formed within the ooplasm. The egg has now
completed meiosis and the FPN is haploid.
(iv)
Sperm
fusion triggers the cortical reaction which involves the exocytosis or release
of cortical granules into the PVS.
(v)
Contents
of released cortical granules interact with the zona – zona reaction - which
chemically hardens the zona to prevent polyspermy. Only one sperm needs to
fertilize the egg.
(vi)
A
sperm aster is formed and the male and female pronuclei migrate to the centre
of the egg, where they associate but do not fuse. Apart from the father’s
chromosomes, the sperm introduces the centriole, which is the active division
centre within the embryo during mitosis (cleavage).
Thus fertilization is a complex process, which
essentially involves activation of the egg to develop further into an embryo
and foetus.
[For diagrams
and illustrations see atlases, Sathnanthan et al, (1993; 1996)]
Fertilization is a complex process, which essentially involves
activation of the egg to develop further into an embryo and foetus.
CLEAVAGE:
REPEATED MITOSES (CELL DIVISION)
Soon after fertilization, the activated egg (ovum) cleaves
as it travels down the oviduct to enter the
uterus. Cleavage involves repeated mitotic divisions
with little or no growth. The ovum or zygote divides into 2, 4, 8, 16, 32 cells
and becomes a morula and blastocyst, when divisions become irregular. The
functional sperm centriole (centrosome) introduced at fertilization replicates
and first forms a sperm aster, which then splits to form a bipolar spindle
about 20 hours after fertilization. The male and female pronuclei, formed ~12 hours after fertilization, dissociate
their envelopes and the paternal and maternal chromosomes come together and
organize themselves on this spindle, a stage called “syngamy”. This establishes
the embryonic genome, which is activated later on between the 4-8 cell stage in
the human. The first cell division occurs around 24 hours after fertilization
and a 2-cell embryo is formed. The embryo then divides into 4, 8, 16, 32 cells
called blastomeres and forms a morula (mulberry), which develops a fluid filled
cavity to become a blastocyst. After the 8-cell stage, the embryo becomes
compact (compaction) when cells increase contact with one another and develop
an inside-outside polarity, which later gives rise to a mass of cells within
the blastocyst - the inner cell mass
that becomes the embryo proper (embryoblast) and an outer layer of cells which
forms an epithelium and gives rise to placental membranes (trophoblast).This is
the first sign of cell differentiation (cells becoming different) in the human
embryo. The morula enters the uterus on day 3-4 of development.
Cleavage involves repeated mitotic divisions with little or no
growth
BLASTOCYST
HATCHING AND SUPERFICIAL IMPLANTATION (DAY 6)
The blastocyst expands as hydrostatic pressure of
fluid increases within its cavity and it hatches out of the zona (day 5)
through a hole believed to be digested by enzymes, and squeezes its way out. It
now closely adheres to the uterine endometrium and trophoblast cells
proliferate and form a syncytiotrophoblast (common cytoplasm with several nuclei)
which invades the uterine epithelium.
The endometrial stroma responds by becoming secretory (decidual reaction), while uterine glands
enlarge and the uterus becomes vascularized and edematous, due to the influence
of progesterone and oestrogen secreted by the corpus luteum of the ovary. After
implantation the trophoblast produces human chorionic gonadotrophin (hCG) which
can be detected in the mother’s urine during the first 2 months of pregnancy
(pregnancy test). Later the placenta secretes progesterone, as well. If there
is no pregnancy the corpus luteum degenerates after about 13 days. The normal
site of implantation is the endometrial lining around the cavity of the uterus
(body of the uterus). Ectopic pregnancies result when the embryo implants
outside this region, e.g., in the tube or cervix – this will be dealt with in
another chapter.
[For diagrams
of cleavage-stage embryos see atlas-
Sathananthan et al (1993); Moore (1989); Langman (1982)]
After implantation the trophoblast produces human chorionic
gonadotrophin (hCG) which can be detected in the mother’s urine
CLINICAL
APPLICATIONS: TREATMENT OF INFERTILITY
The greatest advances in assisted reproduction stem
from the recent development of IVF and ART technologies which has led to a better
understanding of human development in the first week. This was a grey area
before the advent of these techniques. Consequently, we have now an indepth
understanding of the events of fertilization, cleavage and abnormalities,
thereof. Apart from IVF, the single technique that has revolutionized the
treatment of infertility is intracytoplasmic sperm injection (ICSI). This
successful technique of assisted fertilization violates most of the norms of
fertilization since the sperm is injected directly into the oocyte, bypassing
its vestments and pre-empting natural sperm-egg fusion. We have to wait and see
the long term effects of this technology. This will be dealt with at length in
another chapter on subfertility.
Another exciting finding is
the paternal inheritance of the centrosome, which regulates early cleavage in
the human embryo [see atlas,
Sathananthan et al, 1996] which led us to postulate a new theory of
infertility which states that a bad sperm with poor motility may result in a
poor quality embryo, especially after ICSI. This hypothesis is now gaining wide
acceptance both in the human and larger mammals. The male has to share equal
blame for the causes of infertility.
We have now a better understanding of hormonal
interactions and monitoring in the stimulated cycle; embryo development in
vitro including co-culture methods; chromosomal aberrations in gametes and
embryos; uterine receptivity to implantation and, of course, the techniques
that have evolved in gamete recovery, such as ultrasound, embryo transfer and
embryo biopsy after assisted reproduction. The amazing pictures that have been
generated of gametes, fertilization, embryos, and the reproductive tract in
recent years would not have been possible without ART [see Atlas, Sathananthan et al, 1996]
The paternal centrosome regulates cell division in the embryo and is
the active division centre. A maternal
contribution is made in the zygote
THE
SECOND WEEK: Bilaminar embryo: Deep implantation
Most things happen “in twos” during this week.
(i)
Embryoblast splits into two layers (beginning of gastrulation)
(ii) Two new
cavities are formed: amniotic and chorionic
(iii) Trophoblast differentiates into cyto and
syncytio-trophoblast
a) Bilaminar Embryo
The embryo is discoidal and spherical and consists
of two layers: epiblast (above) and hypoblast (below) formed by delamination
(splitting) of a single layer. The hypoblast (day 7) becomes the endoderm and
the epiblast will later differentiate into ectoderm and mesoderm (week 3). The
endoderm proliferates and lines the blastocoele cavity (Heuser’s membrane), now
called the primitive yolk sac below the embryonic disc (day 8). There is no
yolk in the human – yet a yolk sac appears as in yolky embryos, e.g. chick.
However, the yolk sac is vital for formation of blood and germ cells.
b) Amnion and chorion and their
cavities.
These two membranes are foetal (extraembryonic)
membranes while the yolk sac is another. The conceptus at this stage can be
regarded as being composed of 3 balloons – amniotic sac above and yolk sac
below, pressed against the embryonic disc. The chorionic sac is the largest
balloon on the outside (trophoblast), covering the 2 sacs and the embryonic
disc.
The Amnion: The amnion appears on day
8 on the roof of the embryonic disc. Fluid accumulates and a thin epithelium is
formed from the cytotrophoblast. The epiblast forms the floor of the amniotic
cavity. This is the beginning of the water bag. The amniotic cavity enlarges
and by week 8 encloses the entire embryo.
The
Chorion: The chorion is formed after the appearance of the
extraembryonic mesoderm (days 10/11). These
cells arise from the epiblast and migrate to form two layers – the inner
lining the Heuser’s membrane (secondary yolk sac) and the other the inner
surface of the cytotrophoblast which becomes the chorion. The cavity formed is
the extraembryonic coelom or chorionic cavity (days 12/13). The chorionic
cavity enlarges and the embryonic disc with its dorsal amniotic sac and ventral
yolk sac is suspended in the chorionic cavity by a connecting stalk of mesoderm.
[For
diagrams see Moore (1989); Langman (1982); Larsen (1998)]
c) Cyto- and syncytiotrophoblasts
(deep implantation)
The trophoblast has already differentiated into a
cellular (cytotrophoblast-CT) and syncytium
(syncytiotrophoblast-ST) at the embryonic pole of
the blastocyst. The ST is invasive and helps the embryo implant in the
endometrium. Deeper implantation (days 7-9) involves extensive growth of the
conceptus and its complete implantation within the endometrium, leaving a scar
or blood clot (closing plug). Hydrolytic enzymes secreted by the trophoblast
digest the extracellular matrix between the endometrial cells and processes of
the trophoblast penetrate deep into the endometrium. The ST grows all around
the conceptus and lacunae or cavities appear within it (day 9). Soon maternal
blood capillaries anastomose and invade the lacunae establishing a primitive
uteroplacental circulation. Extensions of the CT extend and grow into the
overlying ST establishing the primary chorionic villi (beginnings of the
placenta).
A primitive uteroplacental circulation is established in week 2 not
to be confused with the placenta
d) Clinical Applications
Spontaneous
Abortions:
These are quite common during early development. An abortion is defined as a
termination of pregnancy before 20 weeks of gestation. Almost all abortions
that occur in the first 3 weeks are spontaneous (not induced). It is estimated
that 50% of all such abortions are caused by chromosomal abnormalities. It is also
reported that 30-50% of zygotes never become blastocysts and implant.
Hydatiform
Mole: Few
of the pregnancies result in hydatiform moles in which the embryo is entirely
missing and only a placenta is present. Primary chorionic villi are present without
embryonic vessels – detectable by ultrasound. Complete moles have 46
chromosomes, all of paternal origin because zygotes have two male pronuclei.
Partial moles are formed from triploid dispermic zygotes. Both types of moles
tend to abort spontaneously or are surgically removed. Persistent molar tissue
may result in trophoblastic disease.
THE
THIRD WEEK: Trilaminar embryo –
formation of germ layers.
The most dramatic event in early development is the
formation of the 3 primary germ layers: ectoderm, endoderm and mesoderm –
referred to as gastrulation in animal terms. It is from these 3 germ layers
that all the tissues and organs of the human body are formed. Basically,
ectoderm forms the skin and nervous system (outside), endoderm the gut and associated
glands including the respiratory system (inside), while mesoderm forms all the
other organ systems (in between).
[For details
of derivatives of germ layers see Moore (1989)]
The most dramatic event in early development is the formation of
ectoderm, endoderm and mesoderm, the three germ layers – referred to as
gastrulation
Primitive streak: Mesoderm formation
The embryonic disc now becomes pear-shaped and
develops a linear primitive streak, dorsally in the epiblast, which is a heap of
cells that proliferate and migrate to the centre line. It appears first at the
caudal end at the beginning of week 3 and grows towards the centre of the disc.
The primitive streak (day 16) signals the formation and separation of mesoderm
from the ectoderm overlying it. It may be likened to a permanently closed
keyhole, where cells migrate inwards, sideways and forwards to form the
mesoderm sandwiched between the ectoderm and the endoderm (hypoblast) which was
formed in week 2. This is best appreciated in transverse sections of the disc.
[Excellent 3-D images of the process, as
well as sections, are presented in Langman (1981); Moore (1989); Larsen (1993).
The process of mesoderm formation is called “immigration”, while endoderm
formation is referred to as “delamination”. Both processes result by
differentiation and movement of cells to take up their definitive positions in
the embryo, of course regulated by the genes on the chromosomes of maternal and
paternal origin. The genes control the process of development before and after
birth. Thus cell differentiation and cell movements are integral processes of
development – it is important to put the right cell in the right place at the
right time to ensure normal development. Any disturbances in this co-ordinated
interaction of cells will eventuate in abnormal development. Both genetic and
environmental factors are involved in many developmental processes.
Morphogenesis (the development of complex from simple structure) is regulated
by cascades of gene expression. At first the maternal genes are switched on,
which then activate the zygotic genes. Important events such as gastrulation
are controlled by such genes. The embryo is now trilaminar and after all
mesoderm cells have migrated along the primitive streak it regresses to the
caudal region of the embryo and degenerates. If it persists a tumor or teratoma
is formed.
Gastrulation involves proliferation, differentiation and movement of
cells within the embryo
Neurulation and formation of the
notochord
Neurulation involves the formation of the neural
plate and tube (primitive nervous system). This is preceded by formation of a
hollow rod of cells beneath the ectoderm as the primitive streak recedes. The
mesoderm cells that migrate through the primitive knot (cranial end of streak)
become the notochordal process. This is later transformed into a solid rod –
the notochord, the embryonic axial skeleton - which is replaced by the
vertebral column. On day 17 the notochordal mesoderm induces the overlying
ectoderm to form the neural plate. This is a good example of chemical induction
where one tissue induces the formation of another.
Neural tube formation
At first the neural plate is oval but later
elongates over the underlying notochord along the whole axis
of the embryo. The plate invaginates towards the
notochord to form a neural groove, which deepens progressively to form a tube
by fusion of the lateral neural folds. This nerve tube is hollow and is lined
by pseudostratified columnar epithelium. The cells of the neural crest separate
from the tube to develop into the spinal and autonomic ganglia and pigment
cells, later. The nerve tube is formed on days 19-21, and its closure begins in
the middle of the embryo and progresses towards cranial and caudal ends by the
end of week 4. The anterior end swells to become the brain and the rest forms
the spinal cord. The neural tube is open cranially and caudally, forming the
neuropores, which close in week 4.
The neural tube forms the central nervous system – brain and spinal cord.
Development of somites
Somites are blocks of paraxial mesoderm which appear
in pairs on either side of the notochord.
The first somite appears on day 20 behind the base of the future skull.
This is the first sign of segmentation in the embryo. Subsequent somites form
behind the first progressively till 42-44 pairs are formed by week 4/5. The
number of somites are used to determine the age of the embryo. The somites give
rise to most of the axial skeleton, associated musculature and dermis of the skin.
The intraembryonic coelom (body cavity) is formed in mesoderm lateral to the
somites.
Somites are blocks of mesoderm used to determine embryonic age
Formation of heart and blood vessels
The rudiments of the heart and blood vessels are
also laid down in week 3. Blood vessels are formed in the mesoderm of the yolk
sac and chorion as spaces within mesenchyme cells (blood islands). They are
soon lined with endothelium, and unite with other vessels to form a primitive
cardiovascular system. The heart is formed at the end of week 3 in much the
same way as enlarged blood vessels in the cranial region. Paired heart tubes
are formed which begin to fuse to form a primitive heart, which connects up
with blood vessels in the embryo, chorion and yolk sac. The heart begins to
beat and the vascular system is the first to become functional.
[A diagram of
the primitive vascular system is shown in Moore, 1989]
Allantois
The fourth foetal membrane appears in week 3 as a
diverticulum of the yolk sac (caudal wall). It remains small and is also
involved in angiogenesis (formation of blood vessels) and is later associated
with the development of the urinary bladder.
Chorionic villi
The primary chorionic villi have a core of
connective tissue and eventually develop blood capillaries and become secondary
and tertiary villi and cover the entire surface of the chorion (see placenta).
Their vessels also connect up with vessels inside the embryo. Nutrients and
other substances are exchanged between maternal and foetal circulations.
Blood vessels are formed in the mesoderm of the yolk sac, chorion
and allantois.
Congenital malformations
Disturbances in neurulation cause some abnormalities
of the brain and spinal cord. Failure of
closure of the neural tube in the caudal region (caudal
neuropore) results in spina bifida. These defects also involve the tissues
overlying the spinal cord (meninges, vertebral arches, dorsal musculature and
skin). The most frequent site of failure of neurulation is the cranial
neuropore resulting in anencephaly.
WEEKS
4 – 8:CRITICAL PERIODS OF DEVELOPMENT: Formation of all major organ rudiments and the embryonic body
The last 5 weeks of embryonic development are very
critical since all the main organ systems are laid down, both externally and
internally, and the embryo takes shape and finally takes the characteristic
human form by week 8. It is a critical period since major developmental
disturbances that occur now could result in major congenital malformations in
each system of the human body. During this period the embryo is susceptible to
teratogens (agents that induce malformations).
[A schematic
illustration of critical periods for some organs is presented in Moore (1989)]
Major congenital malformations may occur during the critical periods
of development.
Formation of the embryonic body:
Folding and Flexion
Up to the end of week 3 the embryo was a flat
disc. In week 4, the embryo grows very
rapidly and becomes progressively cylindrical and takes a characteristic
C-shaped form, common to vertebrate embryos. This is caused by folding of the
embryo, cranially, caudally and laterally, at the same time positioning and
demarcating some of the organs within
the embryo.
The effects of folding can best be seen in
longitudinal and transverse sections of embryos [see Langman (1981); Moore
(1989); Larsen (1993)]. Head and tail flexion occurs ventralwards during week
4, raising and demarcating the embryonic body from the disc. The developing
brain grows cranially, tucking the heart and future mouth cavity ventrally.
Part of the yolk sac is incorporated into the embryo as the foregut. Soon the
tail fold at the caudal end projects over the cloacal region and incorporates
part of the yolk sac as the hindgut. After folding, the connecting stalk and
yolk stalk remain attached to the ventral surface of the embryo as the
umbilical cord. Simultaneously the lateral folds establish the almost
cylindrical form of the rest of the embryo – best visualized in transverse
sections. As the lateral folds grow medially, the roof of the yolk sac is
incorporated into the embryo as the midgut, and the yolk sac is reduced to a
narrow yolk stalk. The somites differentiate into sclerotome, myotome and
dermatome components internally and are prominent externally.
The embryonic body is formed by flexion and folding resulting in a
cylindrical embryo.
The C – shaped embryo, thus formed, undergoes
further flexion and growth in weeks 5 and 6. It develops fore and hind limb
buds and a heart prominence in the chest region. The eye develops on the sides
of the forebrain region and 4 branchial arches appear on the sides of the
foregut region (pharynx). The brain has divided into fore, mid and hind brain
compartments and is demarcated from the rest of the spinal cord. The somites
(33-35 pairs) become more prominent on either side of the spinal cord –
evidence of segmental development. The head has grown much larger than the body
in week 6 due to the growth of the brain. The forelimb develops digital rays –
future digits. The external auditory meatus (ear) appears where the first
branchial groove is located. The peripheral nervous system begins to form,
integrating the developing nervous system. Neural crest cells migrate from the
neural tube and aggregate to form ganglia of the sympathetic nervous system and
the sensory spinal ganglia.
The embryo is C-shaped like most other vertebrate embryos, when they
look similar.
During the weeks 7 and 8 limbs have formed, the
fingers of the hand have separated and the feet are webbed, which then separate
into toes. The tail stub disappears altogether. The head is more round and
erect but is disproportionally large. The abdomen is flatter but the intestines
have herniated in the proximal region of the umbilical cord. Eyelids have
formed and are usually open. The auricles of the external ear have formed. The
head has enlarged immensely and the embryo is now unquestionably human in
appearance.
Determination of Embryonic Age and
Measurement
Two criteria are used to determine day 1 in the
natural cycle to estimate age:- time of fertilization or onset of last
menstrual cycle. The latter becomes complicated for those who have discontinued
oral contraception. The day of fertilization is the most reliable for
estimating age and this is easily determined by the time of ovulation + 12
hours, which is the timeframe within which the egg is fertilized. In vitro,
estimation is easier, since fertilization occurs 2 – 3 hours after insemination and pronuclei are formed 12 – 16 hours
after insemination [see atlases,
Sathananthan et al, 1993;1996] Embryonic age is determined from external
features and measurement of length, usually after abortions. Their greatest
length , crown – rump length (sitting height) or crown – heel length are often
used. More accurate measurements can be made in utero by ultrasound at weeks 4
– 5, when external structures can be visualized. [See Moore, 1989, for measurements and tables]
Internal differentiation:
Organogenesis
The 3 germ layers formed from the inner cell mass in
week 3 give rise to all the tissues and organs of the human body. Cells of each
germ layer proliferate, migrate, reaggregate and differentiate into various
tissues that form the organs (organogenesis)
Ectoderm This outermost layer forms
the epidermis of the skin and glands, the central nervous system (brain and
spinal cord), peripheral nervous system (nerves and ganglia), and the sensory
epithelia (eye, ear and nose).
Mesoderm This intermediate layer
forms the majority of tissues and organs: connective, skeletal, muscular
tissues, cardiovascular, urinary and reproductive systems, body cavities and
linings and the spleen.
Endoderm This innermost layer forms
the epithelium of the gastro-intestinal and respiratory systems and associated
glands (liver and pancreas), epithelial lining of urethra and parts of the ear,
thyroid, parathyroid and tonsils.
Critical periods for most organ systems generally
range from 3 – 8 weeks of development, when the rudiments are laid down.
Teratogens kill the embryo in the first two weeks or damage some cells
allowing the embryo to recover [see Moore, 1989]
The 3 germ layers give rise to all the tissues and organs of the
human body.
PHYSIOLOGY
OF THE EMBRYO: Placentation
The placenta is an organ derived from the
trophoblast of the blastocyst and is composed of some foetal
membranes. These membranes are mostly extraembryonic
and consist of the amnion, chorion, yolk sac and allantois, which combine to
various degrees to form the placenta and umbilical cord. Humans are placentals
and the foetal placenta is allanto-chorionic , with the villous chorion forming
the major part of the organ. It is essentially involved in the physiology of
the embryo and has many functions:- protection, nutrition, respiration,
excretion and also has an endocrine function producing hormones. The term
conceptus refers to the embryo plus the foetal membranes.
The decidua.
The placenta has both foetal and maternal components.
The maternal portion is the gravid (pregnant) endometrium, which is cast off at
birth (parturition) – hence termed decidua. The decidua are named acccording to
their relation to the implantation site:- a) Decidua basalis – underlying the
conceptus forming the maternal component; b) Decidua capsularis – the
superficial wall overlying the conceptus;
c) Decidua parietalis – the remaining uterine mucosa or wall. As the
conceptus grows, the capsularis bulges into the uterine cavity and fuses with
the parietalis, obliterating its cavity. The capsularis degenerates and
disappears by about week 22. The basalis forms the maternal placenta and is
usually discoidal in shape.
Development of the placenta
We have already dealt with the origins of the foetal
membranes in weeks 2 and 3. It is by week 4 that the essential parts of the
placenta are established and become functional. By weeks 20 – 22 it is fully
formed [see Moore, 1989, for diagrams].
It is the chorionic villi, embedded in the decidua basalis, that are involved
in foeto-maternal exchanges, later on.
Until about week 8, the chorionic villi (CV) cover the
entire surface of the chorionic sac. Eventually the villi over the decidua
capsularis degenerate due to reduced blood supply, forming the smooth chorion.
Those CV associated with the decidua basalis persist, multiply and branch
profusely to form the villous chorion, the foetal placenta. The foetal
component is thus composed of the chorion and its CV that are bathed in the
maternal blood – hence called a haemo-chorial placenta. The villous chorion,
composed of tertiary villi, is anchored to the maternal decidua basalis by
anchoring villi. The full term placenta has a very complicated structure
composed of branched CV with foetal blood vessels embedded in the decidua
basalis. The CV are bathed with maternal blood filling the intervillous spaces,
flowing from the endometrial spiral arteries, in spurts.
[See Moore,
(1989); Langman, (1981)]
The chorionic villi are the chief
components of the foetal placenta.
Chorionic villi : Villous chorion
Primary CV were formed on day 14 when a primitive
utero-placental circulation became functional. These had a core of
cytotrophoblast (CT) surrounded by syncytiotrophoblast (ST). The core is
eventually invaded by extraembryonic mesoderm, which becomes mesenchyme or
connective tissue (secondary villi) and later by foetal capillaries formed in
week 3 (tertiary villi). These have both CT and ST covering the villus. The
full-term CV has an epithelium of ST with little or no CT and several foetal
capillaries. The whole theme in this development is to make the barrier between
the foetal and maternal blood as thin as possible, to increase the efficiency
of foeto-maternal exchanges. Thus we have arrived at the most efficient
placenta in mammalian evolution and the barrier is called the placental
membrane.[An excellent diagram showing
the embryonic and villous circulatory system is shown in Moore (1989)].
The placental membrane: Villus.
This membrane consists of 4 layers that separate the
foetal from the maternal blood:- foetal capillary
endothelium, foetal connective tissue, CT and ST.
The CT is scanty and the maternal blood bathes the villus. By full term, the
foetal capillaries are brought very close to the maternal blood, there being
little or no intervening connective
tissue.
The placental membrane separates the foetal from the maternal blood.
Foeto-maternal exchanges.
The placenta has three main functions – metabolism, transfer
and endocrine. Many substances can permeate the placental membrane. These
include gases (O2 and CO2) by diffusion; nutrients
(glucose, fatty acids, amino acids, water, electrolytes, vitamins): foetal
waste products (CO2, urea, uric acid); some hormones and antibodies
(IgG) and harmful substances such as drugs, poisons, teratogens, alcohol,
tobacco, cocaine, viruses (rubella) and the syphilis bacterium. Most bacteria
and heparin cannot cross the membrane. HIV could be transmitted across the
placenta during childbirth or by breastfeeding. The placenta also produces
steroid hormones (progesterone and estrogen), human chorionic gonadotrophin (hCG) and other protein hormones and
prostaglandins. Foetal hCG is excreted in the mother’s urine and is the basis
for the pregnancy test.
THE
UMBILICAL CORD
The vascular life-line of the embryo and foetus is
the umbilical cord which connects them to the
placenta. It is gradually formed after week 4,
replacing the connecting stalk and attains a cord-like form by week 20. It is
derived from 3 foetal membranes, amnion, yolk sac and allantois, and the cord
takes shape during extensive growth of the amniotic cavity [best visualized in diagrams-see Moore, 1989]. It is composed of
gelatinous mesenchyme called Wharton’s jelly and usually contains 2 arteries
and 1 vein. The cord usually connects up near the centre of the discoidal
placenta. Knotting or looping of the cord could be dangerous to the foetus,
especially if it is around the neck. It may impede circulation and cause death.
The umbilical cord is the life-line of the embryo and foetus
THE
FOETAL MEMBRANES: Physiology of the embryo.
There are 4 foetal membranes:- chorion, amnion, yolk
sac and allantois. They are extraembryonic in origin and are composed of either
ectoderm or endoderm combined with mesoderm. They play an important role in the
functioning of the embryo and contribute to the formation of the placenta, as
well.
a) Amnion and Amniotic Fluid.
The amnion or waterbag forms a fluid-filled sac
around the embryo and its chief functions are protection, providing an ancient
watery environment, and preventing dessication. All vertebrate embryos develop
in a watery environment and the human is no exception. Amniotic fluid is
derived from the maternal blood and later the foetus excretes urine into the
fluid. The fluid is also swallowed by the foetus and absorbed in the gut. The
embryo floats freely in the fluid, permitting growth and free movement. It
cushions the embryo and acts as a shock absorber. Further it prevents adherence
of membranes and limbs and maintains a constant body temperature.
b) Yolk Sac
Though the human egg has no yolk, it forms a yolk
sac, like the chicken embryo. It develops in week 2 as a sac and is later
reduced to a pear-shaped vestige (week 5). Its functions are:- (i) transfer of
nutrients in weeks 2 and 3 when the utero-placental circulation is established;
(ii) Blood islets form in the mesoderm of the yolk sac wall in week 3
(hemopoietic activity); (iii) The roof of the yolk sac forms the primitive gut
(week 4); (iv) Primordial germ cells appear in the wall of the yolk sac, which
later migrate to gonads to become germ cells.
c) The Allantois
Appears in week 3 as a small
diverticulum in the hindgut region of the embryo and grows into the connecting
stalk. It is non-functional as an embryonic bladder in human embryos but is
involved in the formation of blood during the first 2 months and the allantoic
blood vessels become the umbilical vessels. The allantois also forms the
urachus connected to the bladder which becomes the median umbilical ligament
after birth.
d) The Chorion
This is the most important
foetal membrane, since it forms the foetal placenta – villous chorion, which we
have already dealt with. Above all it is the outermost membrane covering both
the embryo and other foetal membranes. Hence it also has an overall protective
function apart from its placental function. Foetal membranes are
extra-embryonic and are involved in the functioning of the embryo and foetus.
TWINS AND MULTIPLE PREGNANCIES
Multiple pregnancies will be dealt with in another
chapter. However, with respect to foetal membranes, twins may share the amnion
or chorion and even the placenta, depending on whether they are dizygotic or
monozygotic. If dizygotic blastocysts (originating from 2 zygotes) implant
close together, they may share the same placenta. Monozygotic twins
(originating from 1 zygote by division of the inner cell mass) usually have a single
chorion and a common placenta. Monozygotic twins formed by division of the
embryonic disc in week 2 share a single amniotic sac, a chorionic sac and a
placenta. The twins may be separate or conjoined (Siamese) or may be parasitic,
depending on complete or incomplete division of the embryonic disc. Monozygotic
twins are rarely delivered alive since their umbilical cords are entangled when
circulation stops and foetuses die. Twins are usually smaller than a single
foetus, since crowding interferes with growth and nutrition. [See Moore, 1989, for diagrams and
photographs]
SELECTED
REFERENCES
Langman J. Medical embryology (Fourth
Edition) 1981; Williams & Wilkins, Baltimore. pp 384.
(Concise text with colour diagrams and photographs.)
Larsen WJ. Human embryology 1993;
Churchill Livingstone, New York. pp 479
(Advanced text with colour illustrations and
clinical applications)
Moore KL. Before we are born: basic
embryology and birth defects (Third Edition) 1989; Saunders, Philadelphia. pp
306.
(Simple text with colour illustrations and
photographs)
O’Rahilly RA. Colour atlas of human
embryology 1975; Saunders, Philadelphia.
(Comprehensive set of 35 mm slides – the real thing:
whole embryos and sections.)
Sathananthan
AH, Ng SC, Bongso A, Trounson A, Ratnam SS. Visual atlas of early human development for
assisted reproduction technology 1993. National University, Singapore. pp 209
(Pre-implantation development: illustrations and
microphotographs.)
Sathananthan
AH (ed.).
Visual atlas of human sperm structure and function for assisted reproduction
technology 1996; National University, Singapore. pp279.
(Microscopical images of gametes, fertilization and
zygotes, some in colour.)
Sathananthan
AH, Edwards RG. From sperm binding to syngamy – computer enhanced images of human
fertilization (CD-ROM) 1995; Human Reproduction Update 1:1