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Embryology is the study of the development of the embryo and the journey from fertilisation of the egg to the formation of a baby. This is an amazingly complex and delicate process which has impacts on the future health and wellbeing of a child. This article introduces some key concepts in embryology and the key events in the first few weeks of development.
All timings given in this article are approximate and are given in embryological age rather than gestational age. Gestational age is calculated from the mother’s last menstrual period, whereas embryological age is calculated from fertilisation. In practice, this means that gestational age is embryological age + 2 weeks.
It is also important to note that the development in weeks 1 and 2 happens before a pregnancy test would normally be positive. Most tests work from the first day of a missed period, which is about 2 weeks after fertilisation. Pregnancy tests detect a hormone called human chorionic gonadotrophin (hCG). The syncytiotrophoblast (the outer layer of the trophoblast, which goes on to form the placenta) makes hCG. It starts to do so about 6 days after fertilisation, as implantation begins.
The development of the embryo can be divided into 3 stages.
Germinal Stage: fertilisation to the end of week 2. The fertilised egg divides, implants in the uterus and forms a two-layered disc.
Embryonic Stage: weeks 3 to 8. The organ systems begin to form.
Fetal Period: week 9 until birth (term). The organs formed earlier grow and mature.
Fertilisation is the process of fusion between the egg and the sperm. Fertilisation occurs when sperm meet the egg in the fallopian tubes (the tubes that link the ovaries to the uterus), specifically in the ampulla (the widest part of the tube).
Following fertilisation, the first stage of cellular division occurs. The single cell divides into two daughter cells by mitosis. For more information on this process, see our article on mitosis and meiosis. The two daughter cells divide again into 4 cells. These divide into 8, then 16, then 32, and so on. When the solid ball of cells reaches about 16 cells, it is known as the morula. The word ‘morula’ is Latin for ‘mulberry’ because the embryo at this stage resembles this fruit (it looks similar to a raspberry or a blackberry).
In the next few days, the morula continues to divide and becomes known as the blastocyst. The blastocyst has a spherical shape around a fluid-filled cavity and is made up of approximately 100 cells. These cells differentiate into two cell lines: the trophoblast and the embryoblast.
The outer cell mass is called the trophoblast. This tissue’s function is to make contact with the endometrium (the lining of the uterus) and regulate implantation into the uterine wall. Descendants of this structure go on to form the placental tissue.
The inner cell mass is called the embryoblast. This tissue is responsible for the development of the embryo itself.
At this point, the blastocyst is still inside the zona pellucida, the thick glycoprotein layer (a protein with sugar chains attached) that surrounded the egg cell as it was released from the ovary. The blastocyst keeps dividing and growing. It must implant into the uterine wall, but it cannot do this while it is inside the zona pellucida. The zona pellucida will break open to release the blastocyst in a process called ‘hatching’.
Summary of Week 1
- Fertilisation
- Divisions into the morula (16 cells)
- Divisions into the blastocyst (~100 cells)
- Differentiation of the blastocyst into the trophoblast and embryoblast
- Hatching from the zona pellucida.
During the second week of development, the trophoblast and the embryoblast differentiate into specialised cell types:
- The trophoblast differentiates into the syncytiotrophoblast (the outer layer, made of cells that have merged together) and the cytotrophoblast (the inner layer, made of separate cells).
- The embryoblast differentiates into the epiblast (the upper layer) and the hypoblast (the lower layer). The epiblast and the hypoblast together form a flat, two-layered structure called the bilaminar disc.
Around day 6, the blastocyst must implant in the wall of the uterus. During this process, the syncytiotrophoblast invades into the endometrium. It releases enzymes that break down the tissue around it. Spaces called lacunae form in the syncytiotrophoblast and fill with maternal blood. This forms the basis of the placenta.
Implantation normally happens in the superior (upper), posterior (back) or lateral (side) part of the uterine wall. It can happen in other places. If it occurs inferiorly in the uterus, it can block the cervix with the developing placenta, meaning that a fully grown baby would need to push through the placenta to be born vaginally. This condition is called placenta previa (literally ‘placenta first’), and this baby needs to be delivered through Caesarean section to avoid haemorrhage.
In the early weeks the embryo relies mainly on histotrophic nutrition. This is nutrition from the secretions of glands in the lining of the uterus, not from the maternal blood supply. The maternal blood supply to the placenta is not fully established until around the end of the first trimester (the first three months of pregnancy). After that, the fetus relies on haemotrophic nutrition, which is nutrition derived from the maternal blood.
During the second week, the hypoblast contributes to the formation of the primary yolk sac. The chorion develops from the trophoblast and the extraembryonic mesoderm. The extraembryonic mesoderm is supporting tissue that forms outside the embryo.
The primary yolk sac is a membranous sac that lies underneath the bilaminar disc, on the side of the hypoblast. By about day 13 the secondary yolk sac replaces it. The yolk sac is a source of blood cells and of primordial germ cells (the cells that later become eggs or sperm). Part of the secondary yolk sac is taken into the embryo when the embryo folds, and forms the gut.
The chorion is the outer fetal membrane (the membrane that goes on to form part of the placenta). It is formed from the trophoblast and extraembryonic mesoderm. The amnion (the thin membrane around the embryo) develops separately from the epiblast and encloses the amniotic cavity (the fluid-filled space around the embryo).
Summary of Week 2
- Trophoblast differentiates to form the syncytiotrophoblast and the cytotrophoblast.
- Embryoblast differentiates to form the epiblast and the hypoblast, which form the bilaminar disc.
- Syncytiotrophoblast invades the endometrium to form the start of the placenta.
- The hypoblast contributes to the yolk sac, and the chorion forms from the trophoblast and the extraembryonic mesoderm.
In the third week, the bilaminar disc undergoes a process called gastrulation. During gastrulation, the two layers of the disc reorganise into three layers, called the germ layers. These layers go on to form all the tissues and organs of the body.
A new feature develops on the dorsal surface of the epiblast called the primitive streak. This is a line of cells formed by the epiblast that establishes orientation; cephalo-caudal (head to tail) and antero-posterior (front to back). It also marks out the left and right sides of the embryo, which are mirror images of each other (bilateral symmetry). The primitive node forms at the cranial end of the primitive streak. The node controls gastrulation and helps to set up the left-right body axis. The notochord grows forwards from the node.
Under the direction of the primitive streak, the epiblast differentiates into three layers: the ectoderm (the outer layer), the mesoderm (the middle layer) and the endoderm (the inner layer). Together they are known as the trilaminar disc, a disc with three layers.
These three layers go on to form the structures of the body:
The endoderm becomes the internal layer of the body and forms:
- The lining of internal organ systems:
- Respiratory
- Reproductive
- Urinary
- Gastrointestinal
- Specialised cells:
- Pancreas
- Liver
- Thyroid
The mesoderm is the middle layer. It forms the connective tissues (supporting tissues) and muscle throughout the body, for example:
- Cardiac muscle
- Skeletal muscle
- Smooth muscle of the gut and the circulatory system
- Red blood cells
- Notochord - important in development, see later
The extraembryonic mesoderm (the supporting tissue outside the embryo) begins to form in week 2. It spreads around the yolk sac, the chorion and the amnion (the small sac mentioned earlier) to form a supportive layer. You can see this in the part of the diagram in the Summary section labelled ‘Day 18’. The extraembryonic mesoderm also forms a ‘connecting stalk’, which becomes the core of the umbilical cord (the cord that links the fetus to the placenta).
The mesoderm also produces the notochord, a rod of mesoderm that runs from the head end to the tail end (cranio-caudally) down the dorsal side of the embryo. It sits where the spine will be. The notochord secretes growth factors (signalling proteins). These tell the ectoderm above it to become neural tissue, which starts neurulation, the beginning of the development of the central nervous system.
The ectoderm is the outer layer. It becomes the outer covering of the body and the nervous system, for example:
- Epidermal skin cells (the cells of the epidermis, the outer layer of the skin)
- Neurones
- Pigmented cells, like those found on the retina (the light-sensitive layer at the back of the eye)
Diagram - The cell types which develop from each layer of the trilaminar disc
Creative commons source by CNX [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)]
Summary of Week 3
- Gastrulation begins and the primitive streak forms.
- Epiblast differentiates into the endoderm, mesoderm, and ectoderm.
- The mesoderm forms the notochord.
- The extraembryonic mesoderm forms the connecting stalk.
The fourth week is dominated by three main processes:
- Neurulation: the formation of the neural tube, which will go on to become the central nervous system (the brain and spinal cord). It begins in week 3 and is complete by the end of week 4.
- Segmentation: the organisation of somites (paired blocks of mesoderm) to form repeating structures.
- Folding: the folding of the embryo, which turns the flat trilaminar disc into a rounded, tube-like shape.
The process of neurulation and the further development of the nervous system are explained in our article Development of the Nervous System, so they are not covered here.
Segmentation is a process that is driven by somites, which are blocks of mesoderm that run down both sides of the neural tube. They are formed from the paraxial mesoderm, the strips of mesoderm that lie on either side of the notochord and neural tube. The somites develop in a cranio-caudal sequence, beginning in week 3, until there are around 44 pairs by the end of week 5. Some somites regress leaving 31 somites on either side of the neural tube.
The somites have many derivatives:
- The first derivative to specialise from the somites is the sclerotome. This section of each somite helps to form bones such as the vertebrae and the ribs.
- The second derivative is the dermatomyotome, which quickly splits into a dermatome and a myotome. These help form the skin and muscles of the body respectively.
Each somite lies next to a particular level of the neural tube. As the dermatomyotomes develop, each one takes its nerve supply from the spinal nerve at that level. This explains the pattern of innervation (nerve supply) of the skin and muscles in adults.
The somites give the body a repeating, segmented pattern. In the adult, this pattern can be seen in:
- 33 vertebrae: 7 cervical, 12 thoracic, 5 lumbar, 5 sacral and 4 coccygeal. The sacral vertebrae fuse to form the sacrum, and the coccygeal vertebrae form the coccyx. Fusion of the sacrum is not complete at birth. It carries on into early adulthood.
- 31 pairs of spinal nerves. These supply the muscles and the skin in a segmental pattern. A myotome is a group of muscles supplied by a single spinal nerve root. A dermatome is a strip of skin supplied by a single spinal nerve.
For more information, see our musculoskeletal (MSK) article on dermatomes and myotomes.
Folding is the process that turns the trilaminar disc into the shape of an embryo by drawing in the edges of the disc. Two sets of folds occur: cephalocaudal folding (at the head and tail ends) and lateral folding (from both sides). By this point, the neural plate has started to fold to form the neural tube.
When folding begins, the ‘sides’ of the ectodermal layer fold towards each other in the transverse plane. This is called the lateral fold. It forms the trilaminar disc into a tube, with the ectoderm on the outside and the endoderm in the middle of the tube. This movement ‘pinches’ off a portion of the yolk sac. The pinched-off portion ends up in the middle of the tube and goes on to become the gastrointestinal tract (GI tract) of the embryo.
The cephalocaudal folds are at the head and tail ends of the embryo. They form the beginnings of the head and tail. As the disc folds, the foregut and hindgut (the front and back ends of the gut tube) become separated from the yolk sac. The midgut (the middle part of the gut tube) stays open to the yolk sac through the vitelline duct (a narrow tube). This is why there is still a communication between the developing GI tract and the umbilical cord. This will be explained fully in our development of the GI tract article.
See the diagram below to see these changes in action.
Diagram - The stages in the folding of an embryo. It shows the head and tail (cephalocaudal) folds in a sagittal section (left) and the lateral folds in a transverse section (right)
SimpleMed original by Dr. Maddie Swannack
The diagram below shows the progression from fertilisation, through implantation, to the formation of the bilaminar disc. It then shows the differentiation into the trilaminar disc and the eventual folding of the embryo.
Diagram - The first few weeks of human embryogenesis
Creative commons source by Zephyris [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)]
The organ systems begin to form during the embryonic stage (weeks 3 to 8) and keep developing after it. Each one has its own article that explains its development, listed below:
- Development of the Cardiovascular System
- Development of the Reproductive Systems
- Development of the Gastrointestinal Tract
- Development of the Urinary Tract
- Development of the Head and Neck
- Development of the Nervous System
- Development of the Respiratory System
Edited by: Dr. Ben Appleby
Reviewed by: Dr. Thomas Burnell and Dr. Marcus Judge
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