The term “embryo” refers to an organism in the
early stages of its development. In humans, the term is traditionally
reserved for the first two months of development. After that
point, the term “embryo” is replaced by the term
“fetus,” which then applies until birth. Some
authors further reserve the term “embryo” for
the organism only after it has implanted and established its
placental connection to the pregnant woman. Similarly many
also reserve the term “pregnancy” for the state
of the woman only after implantation. At the beginning of
the individual’s development, the entity is a single
cell. After two months, it has limbs, distinct fingers and
toes, internal development, and countless cells. So the term
“embryo” applies to an individual throughout a
vast range of developmental change. This document is a description
of early human development, with emphasis on those events
or structures that have figured most prominently in recent
discussions of research using human embryos or their parts,
especially for stem cell research.1
Development has fascinated centuries of observers, as they
pursued deeper understanding of the stability of species characteristics
at least from one generation to the next, as well as the uniqueness
of each offspring. Uniqueness is especially marked in sexually
reproducing organisms, that is, organisms where the genetic
make-up of the offspring comes from a combination of maternal
and paternal DNA, because a new genome is formed in each instance
of conception. The stability reflects inheritance connecting
one generation with the past and future members of its line.
Organisms and the processes of their development have evolved.
As a result, the development of any organism has a species-specific
pattern, but also shares many of the same developmental processes
with other species related from its evolutionary origins.
Many of the processes discussed here are common not just to
all humans, or to all mammals, but to all vertebrates. In
some cases they are shared even with invertebrates as well.
The process whereby a new individual of the species comes
into being has been at the center of too many deep inquiries
to list here, let alone discuss in the depth they deserve.
But even in this short document it is important to note one
question that is related to the connection of one generation
to the next and previous generations. That is, how are we
to understand the apparent directedness of development, following
a complex network of pathways from a single cell to a multi-system,
free-living, and even conscious being? This process occurs
in a reliable pattern time after time, but also is sufficiently
resilient to perturbations that developing entities can recover
from significant disturbances. For example, at early stages
of development an embryo may divide (or be cut) completely
in half, and then each half recovers to form an entire offspring,
resulting in identical twins.
Different notions of purposive directedness, functional explanation,
and even vital forces have been invoked to explain development.
One of the insights, from the relation of development to evolution,
is that the development of an individual reflects the fact
that it is descended from individuals that reproduced successfully
and, like its forebears whose DNA it inherited, its development
reflects their past survival with their particular characteristics.
This legacy of ancestral success at survival is manifested
in the new organism’s apparent directedness toward development
along lines that enhance its own survival. Even very early
embryos follow patterns of differentiation in the progeny
of different cells. These patterns, in embryology, are called
the fate of the progeny of a cell. The fate of the progeny
of the newest single cell embryo is maximally broad—if
it survives it will give rise to every type of cell of the
species. But as the embryo becomes multicellular, its cells
specialize and, in the absence of artificial perturbation,
their progeny have increasingly specialized fates as well.
The evolved events and processes of development include some
that reflect distant relations, such as the yolk sac that
is conserved in placental mammals, including human beings.
Other events or processes exhibit the evolution of more specific
characteristics. In animals such as human beings, the specialized
and complex membraneous structures that form the connection
between the individual body of the pregnant woman and the
developing individual body of the offspring begin to arise
in the first week. Human embryos implant in the uterine wall
starting at about the sixth day after conception, so of course
they must arrive in the uterus with membranes capable of participating
in that bond. They do not have a fully formed placenta at
such an early stage, nor is the uterine wall unilaterally
ready, but rather the contact of embryo and endometrium initiates
complementary development finally resulting in the fully developed
placenta. One way to look at it is that the early embryo’s
very structure points to the future, showing its overall developmental
fate to be connected to the maternal body. Another perspective
is that this process reflects the past survival of many generations.
In both senses, no moment of development can be understood
in isolation from the context of the organism’s reflection
of its predecessors in evolution, and its directed differentiation
toward its future functioning.
I. GERM CELLS
For the beginning of an embryo, one can look both at the
newly fertilized egg, and also further back, to embryos of
the previous generation. The beginning of an individual is,
of course, the union of egg and sperm, specifically the union
of DNA in the nucleus of each, so as to form a new complete
genome. But the egg and sperm in turn develop from primordial
germ cells that were themselves developed when the parents
of the new individual were embryos. This description starts
at that point (Figure 1).
Developmental cycle, here of a frog. Note the continuity of
germ plasm. [Figure 2.1, page 26, in Gilbert, S. Developmental
Biology. 6th Edition. Sunderland, Mass.: Sinauer Associates
Inc., 2000. Figure reproduced with permission of Sinauer Associates.]
The primordial germ cells are the cells that will give rise
to either ova or sperm. They are large cells with some distinctive
characteristics that make it possible to track them in development.
Note that in Figure 1, they are highlighted throughout the
life cycle of the animal. Primordial germ cells appear in
embryonic development prior to the formation of the gonads
(ovaries in female, or testes in a male). In humans and other
mammals, the primordial germ cells actually develop first
in the yolk sac. In either sex, the primordial germ cells
migrate in through the developing gut of the embryo and then
populate the new gonads of whichever type. In humans, the
primordial germ cells first appear by the end of the fourth
week of development, and begin their migration to the gonads.
The primordial germ cells share certain characteristics with
embryonic stem cells, including self-renewal and pluripotency.
Primordial germ cells have been recovered from fetuses that
were aborted (for reasons unrelated to research) and cell
lines have been established from them, the progeny of which
showed characteristics of multiple different types of cells.2
After the primordial germ cells populate the gonads, some
continue to divide by mitosis, producing more like themselves.
The primordial germ cells are diploid, meaning that they have
all the normal chromosomes of the organism in pairs. In humans,
this means that they have 22 pairs of autosomes, and one pair
of sex chromosomes, or 46 total. Mitosis is the name
of the process whereby the cell replicates its DNA and then
divides equally to result in two cells, each cell including
an entire complement of DNA just like the first cell before
the division (in humans, that is the 46 total chromosomes
mentioned) (Figure 2).
But if a cell is to become an ovum or sperm ready to combine
with a gamete of the complementary type to produce a new organism
(at first a zygote) containing the normal number of chromosomes,
it must undergo a special type of cell division whereby each
gamete acquires only half the diploid number. Each mature
ovum or sperm must include only 23 single (not paired) chromosomes.
Mature ova or sperm cells are haploid, indicating that their
23 chromosomes in their nuclei are unpaired (and after they
combine, then the resulting single cell the zygote is again
diploid). The process whereby the diploid primordial germ
cells develop into haploid gametes is called meiosis
(Figure 3). Mitosis is part of the life cycle of any cell,
but meiosis or meiotic division occurs only in the development
of haploid ova and sperm from diploid primordial germ cells.
The process itself appears as though the cell nucleus is undergoing
two rounds of mitosis, but omits the step of replicating DNA
on the second cycle. In the “first round,” the
differentiating primordial germ cell replicates its DNA, and
then in the “second round” it divides again (without
another replication). In the second division, the pairs of
chromosomes separate, leaving each of the new cells with just
one copy of each of the 22 (in humans) autosomes and just
one sex chromosome.
Figure 2: Schematic
summary of the principal stages in mitotic cell division,
simplified to show the movement of just two pairs of chromosomes.
[Figure 3-4, page 61, in Carlson, B.M. Patten’s
Foundations of Embryology. 4th Edition. New York: McGraw-Hill,
1981. Figure(s) reproduced with permission of the McGraw-Hill
This process does not always occur flawlessly. Errors, such
as failure of the chromosomes to separate properly, sometimes
produce new cells that have the wrong number of chromosomes,
a condition called aneuploidy (that is, not the true number).
One cell may have an extra copy of one of the chromosomes
while the other cell is missing a copy. Such a condition can
be detected in the lab by
Figure 3: Schematic summary
of the major stages of meiosis in a generalized germ cell,
simplified to showing movement of two pairs of chromosomes
at the start. [Carlson, 4th ed., Figure 3-6, p. 64.]
collecting some cells when they are about to go through mitosis
so their chromosomes can be stained and be spread out so their
number and appearance can be examined. A normal set of chromosomes
produces a characteristic picture (22 recognizable pairs and
a pair of sex chromosomes) called the normal karyotype. If
a cell is aneuploid, it will produce an abnormal karyotype
picture. If the aneuploid cell becomes an egg or sperm and
is then involved in a conception, the embryo is also aneuploid.
Aneuploidies are not uncommon events in germ cell development,
but aneuploid survival is uncommon; nearly all aneuploidies
are fatal very early in development.
II. FERTILIZATION AND CLEAVAGE
Like the word “embryo,” the word “conception”
refers to a series of events or processes, not an instantaneous
occurrence. Human development begins after the union of egg
and sperm cells during a process known as fertilization. Fertilization
itself comprises a sequence of events that begins with the
contact of a sperm cell with an egg cell and ends with the
fusion of their two pronuclei (each containing 23 chromosomes)
to form a new diploid cell, called a zygote. Fertilization
normally occurs in the ampulla of the uterine tube
12-24 hours after ovulation (Figure 4).
Before that, however, sperm must travel through the vagina
and the cervix, through the uterus, and then up the uterine
tube. Smooth muscle contractions in the uterine tubes as well
as ciliary activity (waving of hair-like structures) of the
tube’s lining both are important in the transport of
sperm up, and of the ovum into and then down, the uterine
tube. Many more sperm, on the order of tens, or even hundreds,
of millions, are ejaculated than reach the ovum. Those sperm
that do come into the vicinity of the ovum must get through
the material covering the ovum (the corona radiata and the
zona pellucida) and finally contact and bind to the ovum’s
membrane, by means of specialized structures in the head of
the sperm cell. When a sperm does get into the ovum, then
the ovum membrane changes so that other sperm cannot enter.
Meanwhile, the sperm cell in the egg is also undergoing changes
and its specialized structures fall away. The haploid nuclei
of both the sperm and the egg are now called male and female
pronuclei. Both swell, as their densely packed DNA loosens
up prior to replication, and they also migrate toward the
center of the ovum. Then their nuclear membranes disintegrate
and the paternally and maternally contributed chromosomes
pair up, an event called syngamy. In this integration, the
Figure 4A-E: Steps in the
process of fertilization. The sequence of events begins with
contact between a sperm and a secondary oocyte (a mature egg)
in the ampulla of the uterine tube, and ends with formation
of a zygote. [A-E: Fig. 1-1, page 3, in Moore, Essentials
of Human Embryology, 1988, with permission from Elsevier.]
Figure 4F: (see following
page) Shows fertilization, syngamy [from www.visembryo.com
by Mouseworks, Inc.]
4F: Fertilization, Syngamy
In this integration, the diploid chromosome number is
restored, and a new complete genome comes into being.
The result of syngamy is an entity with an individual
genome. Further, if all goes well, it is an entity that
is capable of developing into a fully formed individual
of the species. The fertilized egg is now called a zygote.
It is at this point already entering the first stage
of its first mitotic division, and beginning cleavage
in the Lab
In Vitro Fertilization
(IVF), literally “fertilization in glass”
is the procedure of combining eggs and sperm outside
the body in a dish. The zygotes that are the results
of successful conception, if any, are grown in
culture for a few days and then transferred to
the uterus of the mother. It may be used when
the prospective mother has damaged uterine tubes.
Louise Brown, the first baby from IVF was born
July 25, 1978, in the UK. IVF was put into practice
in the U.S. starting in 1981 and there have since
been over 114,000 U.S. IVF births.
Intracytoplasmic Sperm Injection
(ICSI) is a variation on IVF. Instead of just
allowing sperm and eggs to come into contact in
a dish, a technician physically places a sperm
cell inside the egg cell through the egg membrane.
ICSI is used, among other reasons, when the prospective
father has some condition affecting fertility,
such as a low sperm count.
Usually more eggs are collected
for fertilization than would be transferred at
one time, both to increase likelihood of some
successful conceptions, and because the process
of collecting eggs involves hormonal treatments
that can be uncomfortable and risky for the woman.
Any early embryos that are not transferred right
away are usually stored frozen for later transfer.
But many of these are not transferred. In the
U.S. as of June 2002 there were approximately
400,000 embryos in storage.
Embryo after cleavage.
[www.visembryo.com by Mouseworks, Inc.]
chromosome number is restored, and a new complete genome comes
into being. The result of syngamy is an entity with an individual
genome. Further, if all goes well, it is an entity that is
capable of developing into a fully formed individual of the
species. The fertilized egg is now called a zygote. It is
at this point already entering the first stage of its first
mitotic division, and beginning cleavage (Figure 5).
Like other vertebrates, humans have polarity in three dimensions
(head-tail, or back-front, and left-right). Establishing polarity
of the most basic manifestations of emerging specialization.
But the egg is roughly spherical, and it is not readily apparent
how polarity is established. Although it had been shown long
ago that the point of sperm entry determines the plane of
first cleavage (and thus subsequent ones) in amphibian eggs,
mammals were believed until recently to remain spherically
symmetrical until later in development. Recent data on mammalian
zygotes, however, suggests that the point of sperm entry may
similarly determine the cleavage plane.3
Even the first two cells resulting from the first cleavage
may have different propensities, which persist through the
next divisions as the progeny of one cell tend to become the
body of the offspring and progeny of the other cell become
the embryo’s contribution to the placenta and other
supporting structures. The word “fate,” however,
might be too strong, because the cells of such very early
embryos are resilient to perturbations—if one cell is
removed, the remaining ones can compensate.
After fertilization, the zygote proceeds immediately to the
first cleavage and subsequent cell divisions follow rapidly.
The zygote is a very large cell, but the first waves of rapid
cell division occur without increase in cell volume. The result
is a closely bound mass of cells each of more typical cell
size. At this stage the cells are called blastomeres,
(“parts of the blast,” “blast” coming
from the Greek for “bud” or “germ”)
and the organism as a whole is called a morula (from
the Latin for mulberry, descriptive of its appearance) from
the time it has 16 blastomeres to the next stage. The morula
is still encased in the zona pellucida. As it is undergoing
this very rapid cell division, the organism is also migrating
down the uterine tube toward the uterus. After it arrives
in the uterus, at about day five after the initiation of fertilization,
the zona pellucida breaks up; the process is called
“hatching” and is a necessary prelude to implantation.
Many zygotes do not survive this long. Estimates vary widely
of the rate of natural embryo loss prior to implantation or
after implantation but still early in gestation. One study
of healthy women trying to conceive found 22 percent of pregnancies
(identified by sensitive hormone measures) were lost prior
to becoming detectable clinically. Even after implantation,
there is a substantial rate of loss, still not known precisely
but estimated at 25 to 40 percent.4
When the morula enters the uterus, fluid starts to accumulate
between its blastomeres. The fluid-filled spaces run together,
forming a relatively large fluid-filled cavity. At the point
when the cavity becomes recognizable, the organism is called
a blastocyst (Figure 6). The outer cells of the blastocyst,
especially those around the blastocyst cavity, assume a flattened
shape. The flattened cells of the exterior blastocyst are
the trophoblast. They become the embryo’s contribution
to the placenta and other supporting structures. On one side
of the blastocyst is a group of cells that project inside
into the blastocyst cavity; this is the inner cell mass,
or embryoblast, and its progeny form the body of
the new offspring.
FORMATION OF THE BLASTOCYST
Three stages of the mammalial (blastocyst) of the pig, drawn
from sections to show the formation of the inner cell mass.
[Carlson, 4th Ed., Fig. 4-10, page 124.]
Figure 6D: Early blastocyst
(see following page).
The cells of the inner cell mass can give rise to progeny
differentiating into all the types of cells in the adult body,
so they are called pluripotent. They have not usually been
described as totipotent because, the inner cell mass having
already differentiated from trophoblast, the cells of the
inner cell mass were believed to be no longer able to give
rise to the cells of the trophoblast. Recent work, however,
describes culture conditions under which human embryonic stem
cells can differentiate to trophoblast cells.5
Although the new offspring itself develops only from the inner
call mass, the trophoblast is not just passive padding. Its
progeny are the essential and specialized connection between
the embryonic and maternal systems. Embryonic stem cells can
be isolated from the inner cell mass (see Chapter
IV. TROPHOBLAST TO PLACENTA
After the embyo covering degenerates, the blastocyst, now
in the uterus, enlarges and its trophoblast attaches to the
endometrium (the uterine lining) at about six days after fertilization.
This begins the process of implantation, during which the
blastocyst becomes integrated with the endometrium through
specialized membranes. The embryo is now beginning its second
week of development. The process of implantation takes three
to four days, but is generally completed by day twelve. The
trophoblast area that binds to the endometrium first differentiates
into an inner layer of cells and an exterior layer in which
the membranes dividing the cells degenerate and the cells
fuse. As the blastocyst become more deeply embedded in the
endometrium, the layered area expands until finally the whole
trophoblast surface has divided into one layer or the other.
Meanwhile, a sort of primitive circulation develops, supporting
the embedded blastocyst while more complex structures continue
to develop. The inner cell mass then separates itself from
the overlying trophoblast. The resulting space is called the
amniotic cavity and the layer of cells that forms its roof
is called the amnion (Figure 7).
Another membrane called the chorionic sac develops from the
trophoblast and nearby tissue. Finally, outgrowths of trophoblast
from the chorion project into the endometrium and are called
primary chorionic villi, later giving rise to the placenta.
Although the blastocyst has become completely embedded in
the endometrium and maternal blood bathes the chorionic villi,
the maternal blood does not enter the blastocyst. Later, as
the fetal circulation develops, the fetal and maternal blood
systems still remain distinct and do not mingle. Nutrients,
oxygen, and wastes diffuse in the appropriate direction across
the placenta, but the two blood systems are individual and
do not combine.
Figure 7A: Sections of completely implanted
blastocysts at the end of the second week, illustrating how
the secondary yolk sac forms. The presence of primary chorionic
villi on the wall of the chorionic sac is characteristic of
blastocysts at the end of the second week. A primitive uteroplacental
circulation is now present. [Reprinted from Moore, Essentials
of Human Embryology, 1988, Fig. 2-2, p. 13, with permission
Figure 7B: Photo micrographs
of implantation beginning and completed. [www.visembryo.com
by Mouseworks, Inc.]
The usual case for human beings is for one ovum to be released,
and if all goes well, fertilized and developed to term. Less
commonly, more than one ovum may be released and fertilized
so that more than one embryo develops. These embryos would
be genetically distinct, sharing the uterus during the same
gestation period. They will have a family resemblance but
no more genetic commonality than any other set of siblings,
and they may be of the same or different sexes. These are
called dizygotic twins (because they came from two zygotes).
More rarely, a single zygote may, during its early cleavages,
separate completely into two groups of cells. As discussed
above, the two cells resulting from the first cleavage may
already have different probable fates, the progeny of one
contributing to the body and the other to the supporting structures.
Both, however, at this stage are still totipotent and can,
if disrupted, go on to generate a full individual organism.
If this separation occurs, then monozygotic twins may be born
(Figure 8). Monozygotic twins, two offspring coming from one
zygote, have the same genome and are always of the same sex.
When the twinning occurs in the first cleavages and there
are not yet any extraembryonic membranes (Figure 8A), the
two develop separately as do dizygotic twins, with separate
amnions, chorions and eventually placentae. If an embryo should
divide into two later in its development, between about days
four and eight, the twins will share the same chorion and
therefore eventually the same placenta, but a separate amnion
will form around each (Figure 8B). Should an embryo divide
later than this, between about the ninth and thirteenth days,
the resulting twins will share the same amnion, chorion, and
placenta. It is very rare for embryos to divide still later
than this, but occasionally they do divide after the fourteenth
day. These divisions may not be complete, and then the twins
remain conjoined and can only be surgically separated after
birth (Figure 8C). The twin birth rate in the U.S. has increased
markedly in recent years, and was 30.1 per 1,000 live births
The rate of multiple births (most multiple births are twins;
triplets and so on are more rare) is higher with assisted
reproductive technologies and with higher maternal age. Dizygotic
twins clearly can result in ART from transferring more than
one embryo to the prospective mother. In addition, some assisted
reproductive practices, like age of the embryo transferred,
may be associated with more likelihood of monozygotic twinning,7
though in general the causes of monozygotic twinning are not
Figure 8A-C: Modes of monozygotic
twinning. [Carlson, 4th Ed., Fig. 1-12, page 23]
VI. The primitive streak and Gastrulation
While implantation is occurring, the inner cell mass is also
undergoing changes. First, the inner cell mass separates into
two layers, the epiblast, which is next to the amniotic cavity,
and the hypoblast, which is next to what was the blastocyst
cavity but is by this stage called the primary yolk sac. The
epiblast thus forms the floor of the amniotic cavity (as the
amnion forms the roof) and is connected with the amnion around
the edges. The hypoblast is connected around its edges with
the exocoelomic membrane or primary yolk sac. Thus, the supporting
structures, collectively called the extraembryonic membranes,
are outside of the body that is starting to develop and that
will eventually be born, but during embryonic development
the membranes are also continuous with that body. By the end
of the second week, the hypoblast has developed a thickened
area, called the prochordal plate, that is located at what
will be the cranial (head) end of the individual. In fact,
the prochordal plate shows where the mouth will develop.
As the third week of development begins, dividing cells pile
up in a line to form a thicker band in the epiblast. The line
or band starts nearly directly across from the prochordal
plate, and extends from the edge toward the center of the
embryonic disc. The band is called the primitive streak.
In many policy discussions, the appearance of the primitive
streak is an important boundary. This summary will continue
just a little longer, in order to discuss briefly the nature
of the primitive streak.
The end of the primitive streak that is toward the middle
of the disc (nearer the prochordal plate marking the mouth)
is the cranial end, and this end thickens more as more cells
divide. This especially thick end is called the primitive
knot (formerly called Henson’s node). The end of the
primitive streak near the edge is the caudal (or tail-ward)
end. As a model, think of the primitive streak as a zipper:
the epiblast cells that made the thickness now start to migrate
across the surface and into the zipper of the primitive streak.
As the cells enter the primitive streak, they do a U-turn
around the edge and continue to migrate back the way they
came but underneath the surface, displacing the hypoblast
cells. This movement results in three layers, all of epiblast
origin: what was the epiblast on top, the cells that used
to be part of the epiblast but are now underneath it, and
the cells that remain in between (Figure 9).
These three layers get new names, and they also get newly
specified fates for their progeny. In the same order as above,
they are the ectoderm, mesoderm, and endoderm. The completion
(during the third week after fertilization) of forming these
three layers is called gastrulation. The ectodermal layer
gives rise to progeny fated to become the skin, the nervous
system, and sensory structures of the eye, ear, and nose;
mesoderm gives rise to the skeletal and muscular systems,
connective tissue and blood vessels, and endoderm gives rise
to epithelial parts (e.g., the linings) of the digestive and
Gastrulation is a crucial event in the development of the
body plan of the individual, and it is a stage of development
common to all vertebrates. Our understanding of the significance
of establishing the three germ layers has grown more complex
and subtle over the years. Once interpreted as three completely
separate paths or compartments of development, we now know
that the progeny of the three layers are not totally isolated
in their fates. Cartilage, for example, was once thought to
be entirely of mesodermal origin, but now we know that some
cartilaginous structures of the head and neck come from ectoderm.
Even more recently, work with certain adult stem cell populations
in culture and under special conditions has suggested plasticity
of cell progeny from one germ layer to develop characteristics
of cells typically from another germ layer, long after gastrulation
has assigned the cells of different germ layers their different
fates. Gastrulation is not the first differentiating event:
cells begin to acquire fates for different parts of the developing
embryo before the inner cell mass separates into epiblast
and hypoblast, indeed some results suggest even before the
blastocyst develops an inner cell mass and trophoblast. Yet
these findings in no way detract from the significance of
gastrulation. They rather facilitate our understanding of
gastrulation by placing it in the context of the entire process
of differentiation, beginning from the very earliest stages.
Figure 9A-C: Schematic drawings
of the embryonic disc and its associated extraembryonic membranes
during the third week. A: the amniotic cavity has been opened
to show the primitive streak, a midline thickening of the
epiblast. Part of the yolk sac has been cut away to show the
bilaminar embryonic disc (epiblast and hypoblast). The transverse
section (lower right of A) illustrates the proliferation and
migration of cells from the primitive streak to form embryonic
mesoderm. B and C: drawings illustrating early formation of
the notochordal process from the primitive knot of the primitive
streak. In the longitudinal sections on the right side, note
that the notochordal process grows cranially in the median
plane between the embryonic ectoderm and endoderm. [Reprinted
from Moore, Essentials of Human Embryology, 1988, Fig. 3-1,
page 17, with permission from Elsevier.]
Figure 9D: Photo micrograph
of Primitive Streak
[www.visembryo.com by Mouseworks, Inc.]
Neurulation is the series of developmental events that result
in the beginnings of the central nervous system (Figure 10).
From the cranial end of the primitive streak, a long stiff
structure develops in the mesoderm, elongating still further
in the cranial direction. This becomes the notochord,
which marks the head/tail axis of the embryo. Later, the vertebral
column develops around it. But at this time, the notochord
and its adjacent tissue exert influence called primary
induction on the ectoderm lying over them, such that
the ectoderm thickens and becomes the neural plate.
The neural plate then actually pushes up to form folds (called
the neural folds) along each side of the tissue over the notochord.
The neural folds then meet and fuse to enclose the neural
tube, beginning at the middle of the (future) tube, like a
zipper closing from the middle toward each end. This process
is completed by the end of the third week. Some cells along
the crests of the folds migrate through the embryo. They are
called neural crest cells, and they give rise to a variety
of nerve cells including dorsal root (spinal) and autonomic
nervous system ganglia, and some other nervous system and
Figure 10A-H: Schematic drawings
of the human embryo during the third and fourth weeks. Left
side: Dorsal views of the developing embryo illustrating early
formation of the brain, intraembryonic coelom, and somites.
Right side: Schematic transverse sections illustrating formation
of the neural crest, neural tube, intraembryonic coelom, and
somites. [Reprinted from Moore, Essentials of Human Embryology,
1988, Fig. 3-3, page 20, with permission from Elsevier.]
Neurulation and Notochordal Process
[www.visembryo.com by Mouseworks, Inc.]
The mesoderm still adjacent to the neural tube resolves into
the form of paired blocks on either side of the tube, which
are called somites. The first pair of somites appears
at about the twentieth day after fertilization, at the cranial
end of the neural tube. More pairs appear in the caudal direction,
up until about the thirtieth day. Mesodermal cells from the
somites give rise to most of the skeleton and skeletal muscle.
Blood cell and blood vessel formation actually start at the
beginning of the third week after fertilization, first in
the supportive structures of the yolk sac and chorion. Blood
vessel formation begins in the embryo body about two days
later, although blood is not formed in the embryo itself until
the fifth week. The heart begins as a wide blood vessel, which
later folds up to develop the chambers of the fully formed
heart. But even as a tube, the membranes of its cells have
the electrical and contractile capacity to begin beating in
the third week, and thus to begin primitive circulatory function
with blood. During this time the primary chorionic villi elaborate
branches and form capillary networks and vessels connected
with the embryonic heart. Oxygen and nutrients diffuse from
the maternal blood to the embryonic blood through these capillaries,
while carbon dioxide, urea, and other metabolic wastes diffuse
from the embryonic blood into the maternal blood. Meanwhile,
even firmer connections form between embryonic supporting
membranes and the endometrium, finally completing the development
of the placenta.
The basic structures and relations of all the major organ
systems of the body emerge during the fourth through the eighth
weeks of embryonic development. First, the embryo folds in
several ways so that the flat linear structure distinguished
by neural tube flanked by somites become roughly C-shaped.
The effect of this is to bring the regions of the brain, gut,
and other internal organs into their familiar anatomical relations.
During the fourth week the neural pores, the ends of the neural
tube “zipper,” close. First the one at the cranial
or head end, which is called the anterior or rostral pore,
closes, and later the caudal or tail-ward pore closes. Closure
of the neural pores completes the closure of what will become
the central nervous system. Also during the fourth week, limb
buds become visible, first buds for arms and later for legs.
Further, two accumulations of cells along the neural tube
become distinguishable: the alar plate and the basal plate.
Cells of the alar plate go on to become mostly sensory neurons,
while basal plate cells give rise mostly to motor neurons.
Already while the neural tube is closing, its walls along
the cranial area are thickening to form early brain structure.
Cranial nerves, for example the nerves for the eye and for
the muscles of the face and jaw, also are beginning to develop
at this time. The embryonic brain develops rapidly in both
size and structure especially during the fifth week, and the
optic cup that will form the retina of the eye becomes visible
IX. Conclusion and Continuation
Embryonic development continues with the emergence and differentiation
of organs, the skeleton, limbs, and digits, and with the development
of the face and further differentiation and integration throughout
the body. The development discussed above is summarized briefly
in Table 1.8
But development continues, and is a continuous process, past
the eight-week mark, when the organism is no longer called
an embryo and instead is called a fetus. Although the basic
elements of the body plan have been established during embryogenesis,
a great deal of development of that body plan, refinement
and integration, continues in the fetal stage, also called
phenogenesis (emergence of the normal appearance of the body).
Development continues after birth as well.
|Table1: Summary of
|Pregenesis: develop-ment of parents
||4th week develop-ment
||Parents' primordial germ cells (PGCs)
begin their migration to parents' gonads
week, embryo is unilaminar
||1st cleavages, move to uterus
||Free blastocyst in uterus
||Hatching, start implantation
week, embryo is bilaminar
||Primary stem villi and primitive streak
week, embryo is trilaminar
||Gastrulation begins, notochord forms
||Primitive pit, neural plate, neural groove
||First somites, primitive heart tube
||Neural folds fuse, pulmonary primordium,
||PGCs begin migration, Cranial neuropore
closes, optic vesicles and pit form
||Caudal neuropore closes, arm limb buds
||Leg limb buds, more brain, eye/ear devel.
||5th - 8th weeks
||9th - 38th weeks
1. There are many fine
embryology texts, and the reader is urged to consult one or
more for deeper, broader and more extended treatment of embryology.
The following references are samples only, not a comprehensive
bibliography, selected in part for accessibility to the general
though committed reader, and in part for recent publication.
A few examples concentrating on human embryology would include
Larsen, W. J., Essentials of Human Embryology. New
York: Churchill Livingstone, 1988; Sadler, T. W., Langman’s
Medical Embryology 8th Edition, Philadelphia: Lippincott
Williams and Wilkens, 2002; or Sweeney, L. J., Basic Concepts
in Embryology: A Student’s Survival Guide, New
York: McGraw-Hill, 1988. For a more comparative approach consider
Carlson, B. M., Patten’s Foundations of Embryology.
6th Edition, New York: McGraw-Hill, 1996; and for more comparison
and inclusion of related topics, see Gilbert, S. J., Developmental
Biology, 6th Edition, Sunderland, MA: Sinauer Associates
Inc., 2000. In addition, there are many fine web-based resources,
which the reader is encouraged to visit, for example http://anatomy.med.
unsw.edu.au/cbl/embryo/Embryo.htm and http://www.visembryo.com/
and to accompany Gilbert’s text,
http://www.devbio.com/. These sites provide links to further
resources as well.
2. Shamblott M.J., et
al., “Derivation of pluripotent stem cells from cultured
human primordial germ cells” Proceedings of the
National Academy of Sciences. 95(23): 13726-13731 (1998).
[Erratum in: Proc Natl Acad Sci USA 96(3): 1162 (1999).]
3. Pearson, H., “Your
destiny, from day one.” Nature 418(6893): 14-15
4. Wilcox, A. J., et al.,
“Incidence of early loss of pregnancy,” New
England Journal of Medicine 319(4): 189-194 (1988). See
also this review article: Norwitz, E. R., et al., “Implantation
and the survival of early pregnancy,” New England
Journal of Medicine 345(19): 1400-1408 (2001). Some estimates
are indeed much higher (as high as 80 percent for embryo loss
before and after implantation).
5. Xu, R.H., et al., “BMP4
initiates human embryonic stem cell differentiation to trophoblast”
Nature Biotechnology 20(12): 1261-1264 (2002).
6. National Center for
Health Statistics, “Births: Final Data for 2001.”
National Vital Statistics Reports 51(2) (2002), available
7. Milki, A.A. et al.,
“Incidence of monozygotic twinning with blastocyst transfer
compared to cleavage-stage transfer” Fertility and
Sterility 79(3): 503-506 (2003).
8. Table 1 follows closely
the table of events shown in Larsen (1998), p. xi, and also
the table presented by John M. Opitz, MD, at the January 16,
2003, meeting of the Council. Not all the events listed in
Larsen’s table were included in the Table 1 above, however.